General Information

During the past five decades, dramatic progress has been made in the development of curative therapy for pediatric malignancies. Long-term survival into adulthood is the expectation for 80% of children with access to contemporary therapies for pediatric malignancies.[1] The therapy responsible for this survival can also produce adverse long-term health-related outcomes, referred to as “late effects,” that manifest months to years after completion of cancer treatment. A variety of approaches have been used to advance knowledge about the very long-term morbidity associated with childhood cancer and its contribution to early mortality. These initiatives have utilized a spectrum of resources including investigation of data from population-based registries, self-reported outcomes provided through large-scale cohort studies, and information collected from medical assessments. Studies reporting outcomes in survivors who have been well characterized in regards to clinical status and treatment exposures, and comprehensively ascertained for specific effects through medical assessments, typically provide the highest quality of data to establish the occurrence and risk profiles for late cancer treatment-related toxicity. Regardless of study methodology, it is important to consider selection and participation bias of the cohort studies in the context of the findings reported.

Late effects are commonly experienced by adults who have survived childhood cancer and demonstrate an increasing prevalence associated with longer time elapsed from cancer diagnosis. Population-based studies support excess hospital-related morbidity among childhood cancer survivors compared with age- and gender-matched controls.[3][4][5][6][7] Research has clearly demonstrated that late effects contribute to a high burden of morbidity among adults treated for cancer during childhood, with 60% to almost 90% developing one or more chronic health conditions and 20% to 40% experiencing severe or life-threatening complications during adulthood.[2][8][9][10][11] Recognition of late effects, concurrent with advances in cancer biology, radiological sciences, and supportive care, has resulted in a change in the prevalence and spectrum of treatment effects. In an effort to reduce and prevent late effects, contemporary therapy for the majority of pediatric malignancies has evolved to a risk-adapted approach that is assigned based on a variety of clinical, biological, and sometimes genetic factors. With the exception of survivors requiring intensive multimodality therapy for aggressive or refractory/relapsed malignancies, life-threatening treatment effects are relatively uncommon after contemporary therapy in early follow-up (up to 10 years after diagnosis). However, survivors still frequently experience life-altering morbidity related to effects of cancer treatment on endocrine, reproductive, musculoskeletal, and neurologic function.

Mortality

Late effects also contribute to an excess risk of premature death among long-term survivors of childhood cancer. Several studies of very large cohorts of survivors have reported early mortality among individuals treated for childhood cancer compared with age- and gender-matched general population controls. Relapsed/refractory primary cancer remains the most frequent cause of death, followed by excess cause-specific mortality from subsequent primary cancers and cardiac and pulmonary toxicity.[12][13][14][15][16][17][18]; [19][Level of evidence: 3iA] Despite high premature morbidity rates, overall mortality has decreased over time.[20][21] This reduction is related to a decrease in deaths from the primary cancer without an associated increase in mortality from subsequent cancers or treatment-related toxicities. The former reflects improvements in therapeutic efficacy, and the latter reflects changes in therapy made subsequent to studying the causes of late effects. The expectation that mortality rates in survivors will continue to exceed those in the general population is based on the long-term sequelae that are likely to increase with attained age. If patients treated on therapeutic protocols are followed for long periods into adulthood, it will be possible to evaluate the excess lifetime mortality in relation to specific therapeutic interventions.

Previous studies have shown excess late mortality in childhood cancer survivors. In a population-based study in Finland, the long-term mortality risks from major nonmalignant diseases in 5-year survivors of childhood and adolescent and young adult (AYA) cancer diagnosed before age 35 years were evaluated and included more than 6,000 AYA cancer survivors. In this study, standardized mortality rates (SMRs) were 90% higher for nonmalignant diseases (SMR, 1.9; 95% CI, 1.7–2.2) than expected for the entire cohort, with SMRs similarly elevated for patient subgroups with circulatory disease and respiratory disease. These risks remained elevated for Hodgkin and non-Hodgkin lymphoma survivors diagnosed between the ages of 15 and 34 years. The risk of death from respiratory disease was significantly elevated by 140% (SMR, 2.4; 95% CI, 1.3–4.1) in young adult patients diagnosed with cancer between the ages of 20 and 34 years.[22]

Monitoring for Late Effects

Recognition of both acute and late modality–specific toxicity has motivated investigations evaluating the pathophysiology and prognostic factors for cancer treatment–related effects. The results of these studies have played an important role in changing pediatric cancer therapeutic approaches and reducing treatment-related mortality among survivors treated in more recent eras.[20][21] These investigations have also informed the development of risk counseling and health screening recommendations of long-term survivors by identifying the clinical and treatment characteristics of those at highest risk for treatment complications. The common late effects of pediatric cancer encompass several broad domains including growth and development, organ function, reproductive capacity and health of offspring, and secondary carcinogenesis. In addition, survivors of childhood cancer may experience a variety of adverse psychosocial sequelae related to the primary cancer, its treatment, or maladjustment associated with the cancer experience.

Late sequelae of therapy for childhood cancer can be anticipated based on therapeutic exposures, but the magnitude of risk and the manifestations in an individual patient are influenced by numerous factors. Factors that should be considered in the risk assessment for a given late effect include the following:

Resources to Support Survivor Care

The need for long-term follow-up for childhood cancer survivors is supported by the American Society of Pediatric Hematology/Oncology, the International Society of Pediatric Oncology, the American Academy of Pediatrics, the Children’s Oncology Group (COG), and the Institute of Medicine. Specifically, a risk-based medical follow-up is recommended, which includes a systematic plan for lifelong screening, surveillance, and prevention that incorporates risk estimates based on the previous cancer, cancer therapy, genetic predisposition, lifestyle behaviors, and comorbid conditions.[23][24] Part of long-term follow-up should also be focused on appropriate screening of educational and vocational progress. Specific treatments for childhood cancer, especially those that directly impact nervous system structures, may result in sensory, motor, and neurocognitive deficits that may have adverse consequences on functional status, educational attainment, and future vocational opportunities.[25] A Childhood Cancer Survivor Study (CCSS) investigation observed that treatment with cranial radiation doses of 25 Gy or higher was associated with higher odds of unemployment (health related: odds ratio [OR] = 3.47; 95% confidence interval [CI], 2.54–4.74; seeking work: OR = 1.77; 95% CI, 1.15–2.71).[26] Unemployed survivors reported higher levels of poor physical functioning than employed survivors, had lower education and income, and were more likely to be publicly insured than unemployed siblings.[26] These data emphasize the importance of facilitating survivor access to remedial services, which has been demonstrated to have a positive impact on education achievement,[27] which may in turn enhance vocational opportunities.

In addition to risk-based screening for medical late effects, the impact of health behaviors on cancer-related health risks should also be emphasized. Health-promoting behaviors should be stressed for survivors of childhood cancer, as targeted educational efforts appear to be worthwhile.[28][29][30][31] Smoking, excess alcohol use, and illicit drug use increase risk of organ toxicity and, potentially, subsequent neoplasms. Unhealthy dietary practices and sedentary lifestyle may exacerbate treatment-related metabolic and cardiovascular complications. Proactively addressing unhealthy and risky behaviors is pertinent, as several research investigations confirm that long-term survivors use tobacco and alcohol and have inactive lifestyles at higher rates than is ideal given their increased risk of cardiac, pulmonary, and metabolic late effects.[32][33][34]

Unfortunately, the majority of childhood cancer survivors do not receive recommended risk-based care. The CCSS reported that 88.8% of survivors were receiving some form of medical care; however, only 31.5% reported receiving care that focused on their prior cancer (survivor-focused care), and 17.8% reported receiving survivor-focused care that included advice about risk reduction and discussion or ordering of screening tests.[32] Among the same cohort, surveillance for new cases of cancer was very low in survivors at the highest risk for colon, breast, or skin cancer, suggesting that survivors and their physicians need education about their risks and recommended surveillance.[35] Health insurance access appears to play an important role in access to risk-based survivor care. In a related CCSS study, uninsured survivors were less likely than those privately insured to report a cancer-related visit (adjusted relative risk [RR] = 0.83; 95% CI, 0.75–0.91) or a cancer center visit (adjusted RR = 0.83; 95% CI, 0.71–0.98). Uninsured survivors had lower levels of utilization in all measures of care compared with privately insured survivors. In contrast, publicly insured survivors were more likely to report a cancer-related visit (adjusted RR = 1.22; 95% CI, 1.11–1.35) or a cancer center visit (adjusted RR = 1.41; 95% CI, 1.18–1.70) than were privately insured survivors.[36] In a study comparing health care outcomes for long-term survivors of AYA cancer with young adults who have a cancer history, the proportion of uninsured survivors did not differ between the two groups. Subgroups of AYA survivors may be at additional risk for facing health care barriers. Younger survivors (aged 20–29 years), females, nonwhites, and survivors reporting poorer health faced more cost barriers, which may inhibit the early detection of late effects.[37] Overall, lack of health insurance remains a significant concern for survivors of childhood cancer because of health issues, unemployment, and other societal factors. Legislation, like the Health Insurance Portability and Accountability Act legislation, has improved access and retention of health insurance among survivors, although the quality and limitations associated with these policies have not been well studied.[38][39]

Transition of Survivor Care

Transition of care from the pediatric to the adult health care setting is necessary for most childhood cancer survivors in the United States. When available, multidisciplinary long-term follow-up (LTFU) programs in the pediatric cancer center work collaboratively with community physicians to provide care for childhood cancer survivors. This type of shared-care has been proposed as the optimal model to facilitate coordination between the cancer center oncology team and community physician groups providing survivor care.[40] An essential service of LTFU programs is the organization of an individualized survivorship care plan that includes details about therapeutic interventions undertaken for childhood cancer and their potential health risks, personalized health screening recommendations, and information about lifestyle factors that modify risks. For survivors who have not been provided with this information, the COG offers a template that can be used by survivors to organize a personal treatment summary (see the COG Survivorship Guidelines Appendix 1).

To facilitate survivor and provider access to succinct information to guide risk-based care, COG investigators have organized a compendium of exposure- and risk-based health surveillance recommendations with the goal of standardizing the care of childhood cancer survivors.[23] The COG Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent and Young Adult Cancers are appropriate for asymptomatic survivors presenting for routine exposure-based medical follow-up 2 or more years after completion of therapy. Patient education materials called ‘‘Health Links’’ provide detailed information on guideline-specific topics to enhance health maintenance and promotion among this population of cancer survivors.[41] Multidisciplinary system-based (e.g., cardiovascular, neurocognitive, and reproductive) task forces who are responsible for monitoring the literature, evaluating guideline content, and providing recommendations for guideline revisions as new information becomes available have also published several comprehensive reviews that address specific late effects of childhood cancer.[42][43][44][45][46][47][48][49][50] Information concerning late effects is summarized in tables throughout this summary.

Subsequent Neoplasms

Subsequent neoplasms (SNs), which may be benign or malignant, are defined as histologically distinct neoplasms developing at least 2 months after completion of treatment for the primary malignancy. Childhood cancer survivors have an increased risk of developing SNs that varies by host factors (e.g., genetics, immune function, hormone status), primary cancer therapy, environmental exposures, and lifestyle factors. The Childhood Cancer Survivor Study (CCSS) reported a 30-year cumulative incidence of 20.5% (95% confidence interval [CI], 19.1%–21.8%) for all SNs, 7.9% (95% CI, 7.2%–8.5%) for SNs with malignant histologies (excluding nonmelanoma skin cancer [NMSC]), 9.1% (95% CI, 8.1%–10.1%) for NMSC, and 3.1% (95% CI, 2.5%–3.8%) for meningioma.[1] This represents a sixfold increased risk of SNs among cancer survivors, compared with the general population.[1] SNs are the leading cause of nonrelapse late mortality (standardized mortality ratio = 15.2; 95% CI, 13.9–16.6).[2] The risk of SNs remains elevated for more than 30 years from diagnosis of the primary cancer. Moreover, prolonged follow-up has established that multiple SNs are common among aging childhood cancer survivors.[3]

The development of an SN is likely multi-factorial in etiology and results from combinations of influences including gene-environment and gene-gene interactions. Outcome following the diagnosis of an SN is variable as treatment for some histological subtypes may be compromised if childhood cancer therapy included cumulative doses of agents and modalities at the threshold of tissue tolerance.[4] The incidence and type of SNs differ with the primary cancer diagnosis, type of therapy received, and presence of genetic conditions. Unique associations with specific therapeutic exposures have resulted in the classification of SNs into the following two distinct groups:

Characteristics of t-MDS/AML include a short latency (<10 years from primary cancer diagnosis) and association with alkylating agents and/or topoisomerase II inhibitors.[5][6] Although the long-term risk of subsequent leukemia more than 15 years from primary diagnosis remains significantly elevated (standardized incidence ratio [SIR] = 3.5; 95% CI, 1.9–6.0), these events are relatively rare with an absolute excess risk of 0.02 cases per 1000 person-years.[7] Solid SNs have a strong and well-defined association with radiation and are characterized by a latency that exceeds 10 years.[5] Furthermore, the risk of solid SNs continues to climb with increasing follow-up, whereas the risk of t-MDS/AML plateaus after 10 to 15 years.[8]

Therapy-Related Leukemia

Therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML) has been reported after treatment of Hodgkin lymphoma (HL), acute lymphoblastic leukemia (ALL), and sarcomas, with the cumulative incidence approaching 2% at 15 years after therapy.[8][9][10][11] Some cases of late recurrence among childhood acute lymphoblastic leukemia have been shown to represent cases of new primary leukemia based on TCR gene rearrangement.[12][13] t-MDS/AML is a clonal disorder characterized by distinct chromosomal changes. The following two types are recognized by the World Health Organization classification:[10]

Alkylating agent-related type: Alkylating agents associated with t-MDS/AML include cyclophosphamide, ifosfamide, mechlorethamine, melphalan, busulfan, nitrosoureas, chlorambucil, and dacarbazine.[14] The risk of alkylating agent–related t-MDS/AML is dose dependent, with a latency of 3 to 5 years after exposure; it is associated with abnormalities involving chromosomes 5 (-5/del[5q]) and 7 (-7/del[7q]).[14]

Topoisomerase II inhibitor-related type: Most of the translocations observed in patients exposed to topoisomerase II inhibitors disrupt a breakpoint cluster region between exons 5 and 11 of the band 11q23 and fuse mixed lineage leukemia with a partner gene.[14] Topoisomerase II inhibitor-related t-AML presents as overt leukemia after a latency of 6 months to 3 years and is associated with balanced translocations involving chromosome bands 11q23 or 21q22.[15]

Therapy-Related Solid Neoplasms

Therapy-related solid SNs represent 80% of all SNs and demonstrate a strong relationship with ionizing radiation. The histological subtypes of solid SNs encompass a neoplastic spectrum ranging from benign and low-grade malignant lesions (e.g., NMSC, meningiomas) to high-grade malignancies (e.g., breast cancers, glioblastomas).[1][11][16][17][18] SN solid tumors in childhood cancer survivors most commonly involve the breast, thyroid, central nervous system (CNS), bones, and soft tissues.[1][8][11][17][19] With more prolonged follow-up of cohorts of adults surviving childhood cancer, epithelial neoplasms involving the gastrointestinal tract and lung have emerged.[1][8][16] Benign and low-grade SNs, including NMSCs and meningiomas, have also been observed with increasing prevalence in survivors treated with radiation for childhood cancer.[1][17][18]

The risk of solid SNs is highest when the exposure occurs at a younger age, increases with the total dose of radiation, and with increasing follow-up after radiation.[1] In recipients of a hematopoietic cell transplant conditioned with high-dose busulfan and cyclophosphamide (Bu-Cy), the cumulative incidence of new solid cancers appears to be similar regardless of exposure to radiation. In a registry-based, retrospective, cohort study, Bu-Cy conditioning without total-body irradiation (TBI) was associated with higher risks of solid SNs compared with the general population. Chronic graft-versus-host disease increased the risk of SN, especially those involving the oral cavity.[20] Some of the well-established radiation-related solid SNs include the following:[5]

Skin cancer: NMSCs represent one of the most common SNs among childhood cancer survivors and exhibit a strong association with radiation. Compared to participants who did not receive radiation, CCSS participants treated with radiation had a 6.3-fold increase in risk (95% CI, 3.5–11.3) of reporting a NMSC. Ninety percent of tumors occurred within the radiation field. A CCSS case-control study of the same cohort reported on subsequent basal cell carcinoma. Children who received 35 Gy or more to the skin site had an almost 40-fold excess risk of developing basal cell cancer (odds ratio [OR], 39.8; 95% CI, 8.6–185), compared with those who did not receive radiation; results were consistent with a linear dose-response relationship, with an excess OR per Gy of 1.09 (95% CI, 0.49–2.64).[21] These data underscore the importance of counseling survivors about sun protection behaviors to reduce ultraviolet radiation exposure that may exacerbate this risk.[18] The occurrence of a NMSC as the first SN has been reported to identify a population at high risk for a future invasive malignant SN.[3] CCSS investigators observed a cumulative incidence of a malignant neoplasm of 20.3% (95% CI, 13.0%–27.6%) at 15 years among radiation-exposed survivors who developed NMSC as a first SN compared to 10.7% (95% CI, 7.2%–14.2%) whose first SN was an invasive malignancy.Malignant melanoma has also been reported as a SN in childhood cancer survivor cohorts, although at a much lower incidence than NMSCs. A systematic review including data from 19 original studies (total N = 151,575 survivors; median follow-up of 13 years) observed an incidence of 10.8 cases of malignant melanoma per 100,000 childhood cancer survivors per year. Risk factors for malignant melanoma identified among these studies included radiation therapy or the combination of alkylating agents and antimitotic drugs. Melanomas most frequently developed in survivors of Hodgkin lymphoma, hereditary retinoblastoma, soft tissue sarcoma, and gonadal tumors, but the relatively small number of survivors represented in the relevant studies preclude assessment of melanoma risk among other types of childhood cancer.[22]

Breast cancer: Breast cancer is the most common therapy-related solid SN after HL, largely because of the high-dose chest radiation used to treat HL (SIR of subsequent breast cancer = 25 to 55).[8][23] Excess risk has been reported in female survivors treated with high-dose, extended-volume radiation at age 30 years or younger.[24] Treatment with higher cumulative doses of alkylating agents and ovarian radiation greater than or equal to 5 Gy (exposures predisposing to premature menopause) have been correlated with reductions in breast cancer risk, underscoring the potential contribution of hormonal stimulation on breast carcinogenesis.[25][26] Emerging data indicate that females treated with low-dose, involved-field radiation also exhibit excess breast cancer risk.[27] For female HL patients treated with chest radiation before age 16 years, the cumulative incidence of breast cancer approaches 20% by age 45 years.[8] The latency period after chest radiation ranges from 8 to 10 years, and the risk of subsequent breast cancer increases in a linear fashion with radiation dose (P for trend < .001).[28] Radiation-induced breast cancer has been reported to have more adverse clinicopathological features compared with breast cancer in age-matched population controls.[29] Although currently available evidence is insufficient to demonstrate a survival benefit from the initiation of breast cancer surveillance in women treated with chest radiation for childhood cancer, interventions to promote detection of small and early-stage tumors may improve prognosis, particularly for those who may have more limited treatment options because of prior exposure to radiation or anthracyclines.

Thyroid cancer: Thyroid cancer is observed after neck radiation for HL, ALL, and brain tumors; after iodine I 131 metaiodobenzylguanidine (131I-mIBG) treatment for neuroblastoma; and after TBI for hematopoietic stem cell transplantation.[1][8][30] The risk of thyroid cancer has been reported to be 18-fold that of the general population.[31] Radiation therapy at a young age is the major risk factor for the development of subsequent thyroid cancers. A linear dose-response relationship between thyroid cancer and radiation is observed up to 29 Gy, with a decline in the OR at higher doses, especially in children younger than 10 years at treatment, demonstrating evidence for a cell kill effect.[32][33] Female gender, younger age at exposure, and longer time since exposure are significant modifiers of the radiation-related risk of thyroid cancer.[33]

Brain tumors: Brain tumors develop after cranial radiation for histologically distinct brain tumors [17] or for management of disease among ALL or non-Hodgkin lymphoma patients.[5][34][35] The risk for subsequent brain tumors also demonstrates a linear
relationship with radiation dose.[1][17][35] The risk of meningioma after radiation not only increases with radiation dose but also with increased dose of intrathecal methotrexate.[36] Cavernomas have also been reported with considerable frequency after CNS radiation, but have been speculated to result from angiogenic processes as opposed to true tumorigenesis.[37][38]

Bone tumors: The risk of subsequent bone tumors has been reported to be 133-fold that of the general population, with an estimated 20-year cumulative risk of 2.8%.[39] Survivors of hereditary retinoblastoma, Ewing sarcoma, and other malignant bone tumors are at a particularly increased risk.[40] Radiation therapy is associated with a linear dose-response
relationship.[40][41] After adjustment for radiation therapy, treatment with alkylating agents has also been linked to bone cancer, with the risk increasing with cumulative drug exposure.[40] These data from earlier studies concur with those observed by the CCSS. In this cohort, an increased risk of subsequent sarcoma was associated with radiation therapy, a primary diagnosis of sarcoma), a history of other SNs, and treatment with higher doses of anthracyclines or alkylating agents.[42] The 30-year cumulative incidence of subsequent sarcoma in CCSS participants was 1.08% for survivors who received radiation and 0.5% for survivors who did not receive radiation.

Lung cancer: Among pediatric childhood cancer survivor cohorts, lung cancer represents a relatively uncommon SN; the 30-year cumulative incidence of lung cancer among CCSS participants was 0.1% (95% CI, 0.0%–0.2%).[1] Lung cancer has been reported after chest irradiation for HL. The risk increases in association with longer elapsed time from diagnosis. Smoking has been linked with the occurrence of lung cancer developing after radiation for HL. The increase in risk of lung cancer with increasing radiation dose is greater among patients who smoke after exposure to radiation than among those who refrain from smoking (P = .04).[44]

Gastrointestinal (GI) cancer: There is emerging evidence that childhood cancer survivors develop GI malignancies more frequently and at a younger age than the general population. The Late Effects Study Group reported a 63.9-fold increased risk of gastric cancers and 36.4-fold increased risk of colorectal cancers in adult survivors of childhood HL.[8] In addition to previous radiation therapy, younger age (0–5 years) at the time of the primary cancer therapy significantly increased risk. In a French and British cohort-nested, case-control study of childhood solid cancer survivors diagnosed before age 17 years, the risk of developing a SN in the digestive organs varied with therapy. The SNs most often involved the colon/rectum (42%), liver (24%), and stomach (19%). The risk was 9.7-fold higher compared with population controls and exhibited a strong radiation dose-response relationship with an OR of 5.2 (95% CI, 1.7–16.0) for local radiation doses between 10 Gy and 29 Gy and 9.6 (95% CI, 2.6–35.2) for doses of 30 Gy and above, compared with survivors who had not received radiation. Chemotherapy alone and combined-modality therapy were associated with a significantly increased risk of developing a GI SN (SIR = 9.1; 95% CI, 2.3–23.6; SIR = 29.0; 95% CI, 20.5–39.8).[45] CCSS investigators reported a 4.6-fold higher risk for GI SNs among their study participants compared with the general population (95% CI, 3.4–6.1). The most prevalent GI SN histology was adenocarcinoma (56%). The SNs most often involved the colon (39%), rectum/anus (16%), liver (18%), and stomach (13%). The highest risk for GI SNs was associated with abdominal radiation (SIR = 11.2; CI, 7.6–16.4), but survivors not exposed to radiation also had a significantly increased risk (SIR = 2.4; CI, 1.4–3.9). High-dose procarbazine (relative risk [RR] = 3.2; CI 1.1–9.4) and platinum drugs (RR = 7.6; CI, 2.3–25.5) independently increased the risk for GI SNs. The SIR for colorectal cancer was 4.2 (CI, 2.8–6.3).[46]St. Jude Children's Research Hospital investigators observed that the incidence of a subsequent colorectal carcinoma increased steeply with advancing age, with a 40-year cumulative incidence of 1.4% ± 0.53% among the entire cohort (N = 13,048) and 2.3% ± 0.83% for 5-year survivors. The SIR for subsequent colorectal carcinoma was 10.9 (95% CI, 6.6–17.0) compared with U.S. population controls. Colorectal carcinoma risk increased by 70% with each 10 Gy increase in radiation dose and increasing radiation volume also increased risk. Treatment with alkylating agent chemotherapy was also associated with an 8.8-fold excess risk of subsequent colorectal carcinoma. Collectively, these studies support the need for initiation of colorectal carcinoma surveillance at a young age among survivors receiving high-risk exposures.[47]

Subsequent Neoplasms and Genetic Susceptibility

Literature clearly supports the role of chemotherapy and radiation in the development of SNs. However, interindividual variability exists, suggesting that genetic variation has a role in susceptibility to genotoxic exposures, or that genetic susceptibility syndrome confers an increased risk of cancer, such as Li-Fraumeni syndrome. Previous studies have demonstrated that childhood cancer survivors with either a family history of cancer, but more so, presence of Li-Fraumeni syndrome, carry an increased risk of developing an SN.[48][49] The risk of SNs could potentially be modified by mutations in high-penetrance genes that lead to these serious genetic diseases (e.g., Li-Fraumeni syndrome).[49] However, the attributable risk is expected to be very small because of the extremely low prevalence of mutations in high-penetrance genes. Table 1 below summarizes the spectrum of neoplasms, affected genes, and Mendelian mode of inheritance of selected syndromes of inherited cancer predisposition.

Drug-metabolizing enzymes and DNA repair polymorphisms

The interindividual variability in risk of SNs is more likely related to common polymorphisms in low-penetrance genes that regulate the availability of active drug metabolites or are responsible for DNA repair. Gene-environment interactions may magnify subtle functional differences resulting from genetic variations.

Drug-metabolizing enzymes

Metabolism of genotoxic agents occurs in two phases. Phase I involves activation of substrates into highly reactive electrophilic intermediates that can damage DNA, a reaction principally performed by the cytochrome p450 (CYP) family of enzymes. Phase II enzymes (conjugation) function to inactivate genotoxic substrates. The phase II proteins comprise the glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase-1 (NQO1), and others. The balance between the two sets of enzymes is critical to the cellular response to xenobiotics; for example, high activity of a phase I enzyme and low activity of a phase II enzyme can result in DNA damage.

DNA repair polymorphisms

DNA repair mechanisms protect somatic cells from mutations in tumor suppressor genes and oncogenes that can lead to cancer initiation and progression. An individual’s DNA repair capacity appears to be genetically determined.[51] A number of DNA repair genes contain polymorphic variants, resulting in large interindividual variations in DNA repair capacity.[51] Evaluation of the contribution of polymorphisms influencing DNA repair to the risk of SN represents an active area of research.

Screening and Follow-up for Subsequent Neoplasms

Vigilant screening is important for those at risk.[52] Because of the relatively small size of the pediatric cancer survivor population and the prevalence and time to onset of therapy-related complications, undertaking clinical studies to assess the impact of screening recommendations on the morbidity and mortality associated with the late effect is not feasible. However, well-conducted studies on large populations of childhood cancer survivors have provided compelling evidence linking specific therapeutic exposures and late effects. This evidence has been used by several national and international cooperative groups (Scottish Collegiate Guidelines Network, Children’s Cancer and Leukaemia Group, Children's Oncology Group [COG]) to develop consensus-based clinical practice guidelines to increase awareness and standardize the immediate care needs of medically vulnerable childhood cancer survivors. The COG Guidelines employ a hybrid approach that is both evidence-based (utilizing established associations between therapeutic exposures and late effects to identify high-risk categories) and grounded in the collective clinical experience of experts (matching the magnitude of the risk with the intensity of the screening recommendations). The screening recommendations in these guidelines represent a statement of consensus from a panel of experts in the late effects of pediatric cancer treatment.[52]

In regard to screening for malignant SNs recommended by the COG Guidelines, certain high-risk populations of childhood cancer survivors merit heightened surveillance due to predisposing host, behavioral, or therapeutic factors.

Screening for leukemia: t-MDS/AML usually manifests within 10 years following exposure. Recommendations include monitoring with annual complete blood count for 10 years after exposure to alkylating agents or topoisomerase II inhibitors.

Screening after radiation exposure: Most other SNs are associated with radiation exposure. Screening recommendations include careful annual physical examination of the skin and underlying tissues in the radiation field. Specific comments about screening for more common radiation-associated SNs follow: Screening for early-onset skin cancer: Annual dermatological exam should focus on skin lesions and pigmented nevi in the radiation field. Survivors should be counseled about their increased risk of skin cancer, the potential exacerbation of risk through tanning, and the benefits of adhering to behaviors to protect the skin from excessive ultraviolet radiation exposure.Screening for early-onset breast cancer: Since outcome after breast cancer is directly linked to stage at diagnosis, close surveillance resulting in early diagnosis should confer survival advantage.[53] Mammography, the most widely accepted screening tool for breast cancer in the general population, may not be the ideal screening tool by itself for radiation-related breast cancers occurring in relatively young women with dense breasts; hence, the American Cancer Society recommends including adjunct screening with magnetic resonance imaging (MRI).[54] Many clinicians are concerned about potential harms related to radiation exposure associated with annual mammography in these young women. In this regard, it is important to consider that the estimated mean breast dose with contemporary standard two-view screening mammograms is about 3.85 mGy to 4.5 mGy.[55][56][57] Thus, 15 additional surveillance mammograms from age 25 to 39 years would increase the total radiation exposure in a woman treated with 20 Gy of chest radiation to 20.05775 Gy. The benefits of detection of early breast cancer lesions in high-risk women must be balanced by the risk predisposed by a 0.3% additional radiation exposure. To keep young women engaged in breast health surveillance, the COG Guideline recommendations for females who received radiation with potential impact to the breast (i.e., radiation doses of 20 Gy or higher to the mantle, mediastinal, whole lung, and axillary fields) include monthly breast self-examination beginning at puberty; annual clinical breast examinations beginning at puberty until age 25 years; and a clinical breast examination every 6 months, with annual mammograms and MRIs beginning 8 years after radiation or at age 25 years (whichever occurs later).Screening for early-onset colorectal cancer: Screening of those at risk for early-onset colorectal cancer (i.e., radiation doses of 30 Gy or higher to the abdomen, pelvis, or spine) should include colonoscopy every 5 years beginning at age 35 years or 10 years following radiation (whichever occurs later).

Late Effects of the Cardiovascular System

Radiation, chemotherapy, and biologic agents, both independently and in combination, increase the risk of cardiovascular disease in survivors of childhood cancer; in fact, cardiovascular death has been reported to account for 26% of the excess absolute risk of death by 45 or more years from diagnosis in adults who survived childhood cancers, and is the leading cause of noncancer mortality in select cancers such as Hodgkin lymphoma (HL).[1][2] During the 30 years after cancer treatment, survivors are eight times more likely to die from cardiac causes and 15 times more likely to be diagnosed with congestive heart failure (CHF) than the general population.[3][4] Therapeutic exposures conferring the highest risk are the anthracyclines (doxorubicin, daunorubicin, idarubicin, epirubicin, and mitoxantrone) and thoracic radiation. The risks to the heart are related to cumulative anthracycline dose, method of administration, amount of radiation delivered to different depths of the heart, volume and specific areas of the heart irradiated, total and fractional irradiation dose, age at exposure, latency period, and gender.

Radiation Therapy

The effects of thoracic radiation therapy are difficult to separate from those of anthracyclines because few children undergo thoracic radiation therapy without the use of anthracyclines. However, several reports do allow some segregation of the effects of radiation from those of chemotherapy. Of note, the pathogenesis of injury differs, with radiation primarily affecting the fine vasculature of the heart and anthracyclines directly damaging myocytes.[5][6] Late effects of radiation to the heart include the following:[7][8][9]

Delayed pericarditis, which can present abruptly or as a chronic pericardial effusion.

Pancarditis, which includes pericardial and myocardial fibrosis, with or without endocardial fibroelastosis.

These cardiac toxic effects are related to total radiation dose, individual radiation fraction size, and the volume of the heart that is exposed. Modern radiation techniques allow a reduction in the volume of cardiac tissue incidentally exposed to the higher radiation doses. This may translate into a reduced risk for adverse cardiac events.

Anthracycline Therapy

Increased risk of anthracycline-related cardiomyopathy is associated with the following:[10][11][12][13][14][15][16][17][18][19][20][21][22]

Female gender.

Cumulative doses greater than 200 mg/m2 to 300 mg/m2.

Younger age at time of exposure.

Increased time from exposure.

Among these factors, cumulative dose appears to be the most significant in regard to risk of CHF, which develops in less than 5% of survivors after anthracycline exposure of less than 300 mg/m2, approaches 15% at doses between 300 and 500 mg/m2, and exceeds 30% for doses greater than 600 mg/m2.[5][12][23][24][25]

Schedule of administration of doxorubicin may influence risk of cardiomyopathy. One study looked at the effect of continuous (48 hour) versus bolus (1 hour) infusions of doxorubicin in 121 children who received a cumulative dose of 360 mg/m2 for treatment of acute lymphoblastic leukemia (ALL) and found no difference in the degree or spectrum of cardiotoxicity in the two groups. Because the follow-up time in this study was relatively short, it is not yet clear whether the frequency of progressive cardiomyopathy will differ between the two groups over time.[15] Another study compared cardiac dysfunction in 113 children who received doxorubicin either by single-dose infusion or by a consecutive divided daily-dose schedule. The divided-dose patients received one-third of the total cycle dose over 20 minutes for 3 consecutive days. Patients treated according to a single-dose schedule received the cycle dose as a 20-minute infusion. There was no significant difference in the incidence of cardiac dysfunction between the divided-dose and single-dose infusion groups.[11] Earlier studies in adults have shown decreased cardiotoxicity with prolonged infusion; thus, further evaluation of this question is warranted.[26]

Prevention or amelioration of doxorubicin-induced cardiomyopathy is clearly important because the continued use of doxorubicin is required in cancer therapy. Dexrazoxane is a bisdioxopiperazine compound that readily enters cells and is subsequently hydrolyzed to form a chelating agent. Evidence supports its capacity to mitigate cardiac toxicity in patients treated with doxorubicin.[27][28][29][30][31] Studies suggest that dexrazoxane is safe and does not interfere with chemotherapeutic efficacy.[31] There is a single-study experience suggesting that there could be an increase in malignancies when multiple topoisomerase inhibitors are administered in close proximity; other studies, however, do not show increased risk of malignancies.[31][32][33][34] However, at this time, this should not preclude treatment with dexrazoxane.[35][36]

Two closed Pediatric Oncology Group therapeutic phase III studies for Hodgkin lymphoma (HL) [36][37] measured myocardial toxicity clinically and sequentially over time by echocardiography and electrocardiography, and by determination of levels of
cardiac troponin T (cTnT), a protein that is elevated after myocardial damage.[30][38][39][40][41][42] Long-term outcomes for these patients are not yet available.

The angiotensin-converting enzyme inhibitor enalapril has been used in the attempt to ameliorate doxorubicin-induced left ventricular dysfunction. Although a transient improvement in left ventricular function and structure was noted in 18 children, left ventricular wall thinning continued to deteriorate; thus, the intervention with enalapril was not considered successful.[29] For this reason, studies
to date in doxorubicin-treated cancer survivors have not demonstrated a benefit of enalapril in preventing progressive cardiac toxicity.[28][29]

A number of studies have examined cardiac function after radiation therapy and doxorubicin exposure using cardiopulmonary exercise stress tests and have found abnormalities in exercise endurance, cardiac output, aerobic capacity, echocardiography during exercise testing, and ectopic rhythms.[43][44][45][46][47] In addition to subclinical abnormalities of systolic function observed by conventional echocardiography, diastolic dysfunction (impaired ventricular relaxation) has also been observed, which may precede impairment of systolic function.[48] Specific abnormalities of cardiac function may progress over time after therapy, as suggested by a report targeting parameters of left ventricular contractility.[49] An increased prevalence of diastolic dysfunction has also been reported in childhood cancer survivors, consistent with the hypothesis of increased vascular and ventricular stiffness associated with precocious cardiovascular aging.[50] It remains unclear whether these abnormalities will have clinical impact. Asymptomatic cardiac toxic effects can be demonstrated in patients who have normal clinical assessments, and abnormalities can be linked to lower self-reported health and New York Heart Association cardiac function scores.[51][52] Clearly, additional studies with long-term follow-up will be necessary to determine optimal screening modalities and frequencies.

Compared with siblings, survivors of childhood cancer were significantly more likely to report CHF (hazard ratio [HR] = 5.9; 95% confidence interval [CI], 3.4–9.6), MI (HR = 5.0; 95% CI, 2.3–10.4), pericardial disease (HR = 6.3; 95 % CI, 3.3–11.9), or valvular abnormalities (HR = 4.8; 95 % CI, 3.0–7.6). Cardiac radiation exposure of 15 Gy or more increased the risk of CHF, MI, pericardial disease, and valvular abnormalities by twofold to sixfold compared with nonirradiated survivors.[53] There was no evidence for increased risk following doses less than 5 Gy, and slight elevations in risk were not statistically significant following doses between 5 to 15 Gy. Exposure to 250 mg/m2 or more of anthracyclines also increased the risk of CHF, pericardial disease, and valvular abnormalities by two to five times compared with survivors who had not been exposed to anthracyclines. The cumulative incidence of adverse cardiac outcomes in childhood cancer survivors continued to increase up to 30 years after diagnosis and ranged from about 2% to slightly over 4% overall, but to much higher cumulative percentages for those receiving the highest cardiac radiation doses and the highest cumulative dose of anthracyclines.[53]

A study of 4,122 5-year survivors of childhood cancer diagnosed before 1986 in France and the United Kingdom also provides evidence for an association between radiation dose and risk of cardiovascular disease.[54] After 86,453 person-years of follow-up (average, 27 years), 603 deaths had occurred. The overall standardized mortality ratio was 8.3-fold (95% CI, 7.6–9.0) higher in relation to the general populations in France and the United Kingdom. Thirty-two patients had died of cardiovascular diseases, which is fivefold (95% CI, 3.3–6.7) more than expected. The risk of dying of cardiac diseases (n = 21) was significantly higher in individuals who had received a cumulative dose of anthracyclines greater than 360 mg/m2 (relative risk [RR] = 4.4; 95% CI, 1.3–15.3) and following an average radiation dose exceeding 5 Gy (RR = 12.5 for 5–14.9 Gy and RR = 25.1 for >15 Gy) to the heart. A linear relationship was found between the average dose of radiation to the heart and the risk of cardiac mortality (excess RR at 1 Gy, 60%).

Subclinical cardiac function was evaluated by a group from the Netherlands. Of 601 eligible adult 5-year childhood cancer survivors, 525 (87%) had an echocardiogram performed, of which 514 were evaluable for assessment of the left ventricular shortening fraction (LVSF).[20] The median overall LVSF in the whole group of childhood cancer survivors was 33.1% (range, 13.0%–56.0%). Subclinical cardiac dysfunction (LVSF <30%) was identified in 139 patients (27%). In a multivariate linear regression model, LVSF was reduced with younger age at diagnosis, higher cumulative anthracycline dose, and radiation to the thorax. High-dose cyclophosphamide and ifosfamide were not associated with a reduction of LVSF.

Cardiovascular Disease in Select Cancer Subgroups

Hodgkin lymphoma

Hodgkin lymphoma (HL) continues to be the pediatric malignancy associated with the greatest risk of cardiovascular disease, with a 13.1 excess absolute risk per 10,000 person years for cardiovascular death.[55] Newer treatment approaches are specifically designed to reduce exposure to cardiotoxic agents (e.g., total anthracycline dose) and radiation dose and volume. Moreover, newer trials explore the safe elimination of radiation from primary therapy.

Data from the German-Austrian DAL-HD studies show a dose response for cardiac diseases in children treated for HL with combined radiation and anthracycline-based chemotherapy (cumulative doxorubicin dose was uniformly 160 mg/m2). The 25-year cumulative incidence of cardiac diseases was 3% with no radiation therapy, 5% after 20 Gy, 6% after 25 Gy, 10% after 30 Gy, and 21% after 36 Gy.[56] An older study of 635 patients treated for childhood HL confirms the risks that occur after higher-dose radiation therapy. The actuarial risk of pericarditis requiring pericardiectomy was 4% at 17 years posttreatment (occurring only in children treated with higher radiation doses). Only 12 patients died of cardiac disease, including seven deaths from acute MI; however, these deaths occurred only in children treated with 42 Gy to 45 Gy.[57] In an analysis of 48 asymptomatic patients treated for HL from 1970 to 1991 with mediastinal therapy (median dose 40 Gy) and screened for the presence of subclinical cardiac abnormalities, 43% had unsuspected valvular abnormalities, 75% had a conduction abnormality or arrhythmia, and 30% had reduced VO2 during exercise tests. These abnormalities were noted at a mean of 15.5 years posttherapy suggesting that survivors of HL treated with high doses of mediastinal radiation therapy require long-term cardiology follow-up.[27] Among children treated with 15 Gy to 26 Gy, none developed radiation-associated cardiac problems.[57]

The risk of delayed valvular and CAD after lower radiation doses requires additional study of patients followed for longer periods of time to definitively ascertain lifetime risk. Nontherapeutic risk factors for CAD—such as family history, obesity, hypertension, smoking, diabetes, and hypercholesterolemia—are likely to impact the frequency of disease.[7][8][58]

Other malignancies

Brain tumor: A study of self-reported late effects among 1,607 survivors of childhood brain tumors [59] showed that 18% of survivors reported a heart or circulatory late effect. Risk was highest among those treated with surgery, radiation therapy, and chemotherapy compared with surgery and radiation therapy alone, suggesting a potential additive vascular injury from chemotherapy. Children who receive spinal radiation for treatment of central nervous system tumors have been demonstrated to show low maximal cardiac index on exercise testing and pathologic Q-waves in inferior leads on ECG testing, and higher posterior-wall stress.[60]

Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML): In a study of ALL survivors reporting a chronic medical condition in the CCSS cohort, the risk of a cardiac condition was nearly sevenfold higher compared with the siblings. No significant association was identified based on radiation exposure. A similar analysis among AML survivors in the cohort found the 20-year cumulative incidence of cardiac disease to be 4.7%. It is noteworthy that adult survivors of childhood ALL have an increased prevalence of obesity and insulin resistance and may be at risk for developing diabetes, dyslipidemia, and metabolic syndrome, all known to be potent risk factors for premature cardiovascular disease.[61]

Wilms tumor: A long-term follow-up study of Wilms tumor survivors reported a cumulative risk of CHF of 4.4% at 20 years for those who received doxorubicin as part of their initial therapy and 17.4% at 20 years when doxorubicin was received as part of therapy for relapsed disease. Risk factors for CHF in this cohort included female gender, lung irradiation with doses 20 Gy or higher, left-sided abdominal irradiation, and doxorubicin dosage of 300 mg/m2 or more.[10]

Hematopoietic cell transplantation (HCT): Cardiac complications after bone marrow transplantation may occur, with arrhythmia, pericarditis, and cardiomyopathy predominating, although many are either acute or subacute effects. High-dose cyclophosphamide clearly is a causative agent; total-body irradiation is a secondary contributing factor.[43][58][62] In a report from the Bone Marrow Transplant Survivors Study that compared 145 HCT survivors, 7,207 conventionally treated survivors, and 4,020 siblings from the CCSS cohort,[63] median time from HCT to study participation was 11.0 years (range, 2.3–25.9 years). The prevalence of cardiovascular conditions (grades 3–5) was 4.8% in HCT survivors, versus 3.2% in conventionally treated CCSS survivors, and it was 0.5% (for grades 3–4) in the sibling control CCSS cohort. The RR was 0.5 (95% CI, 0.1–2.5) for the conventionally treated survivors versus HCT survivors, and 12.7 (95% CI, 5.4–30.0) for the HCT survivors versus siblings.

Vascular Disease/Cerebrovascular Accident

A spectrum of vascular morbidities may occur after radiation therapy used to treat malignancies such as lymphomas, head and neck cancers, and brain tumors. Specifically, carotid artery and cerebrovascular injury occur after cervical and central nervous system irradiation. French investigators observed a significant association with radiation dose to the brain and long-term cerebrovascular mortality among 4,227 five-year childhood cancer survivors (median follow-up, 29 years). Survivors who received more than 50 Gy to the prepontine cistern had an HR of 17.8 (95% CI, 4.4–73) of death from cerebrovascular disease compared with those who had not received radiation therapy or who had received less than 0.1 Gy in the prepontine cistern region.[64] The RR for cerebrovascular accident (CVA [stroke]) in the CCSS cohort was almost tenfold higher compared with the sibling control group;[4] notably, risks were highest among the adult survivors of childhood ALL, brain tumors, and HL.[65][66] Leukemia survivors were six times more likely to suffer a CVA compared with their siblings, whereas brain tumor survivors were 29 times more likely to suffer a CVA. Of the brain tumor cohort, 69 of 1,411 patients who had a history of radiation therapy reported a CVA (4.9%), with a cumulative incidence of 6.9% (95% CI, 4.47–9.33) at 25 years. Survivors exposed to cranial radiation therapy greater than 30 Gy had an increased risk for CVA, with the highest risk among those treated with greater than 50 Gy.[66] Adult survivors of childhood HL who were treated with thoracic radiation therapy, including mediastinal and neck, had a 5.6-fold increased risk for CVA than their siblings (median dose 40 Gy).[65] In another study from the Netherlands of 2,201 5-year survivors of HL (of whom 547 were younger than 21 years), and with median follow-up of 17.5 years, 96 patients developed cerebrovascular disease (55 CVA, 31 transient ischemic attacks [TIA], and 10 both CVA and TIA), with a median age at diagnosis of 52 years.[67] Most ischemic events were from large-artery atherosclerosis (36%) or cardioembolism (24%). The standardized incidence ratio (SIR) for CVA was 2.2, and for TIA it was 3.1. The cumulative incidence of ischemic CVA or TIA 30 years after HL treatment was 7%. For patients younger than 21 years, the SIR for CVA was 3.8, and for TIA it was 7.6. Radiation to the neck and mediastinum was an independent risk factor for ischemic cerebrovascular disease (HR = 2.5; 95% CI, 1.1–5.6) versus without radiation therapy. Treatment with chemotherapy was not associated with increased risk. It is noteworthy that hypertension, diabetes mellitus, and hypercholesterolemia were associated with the occurrence of ischemic cerebrovascular disease, whereas smoking and overweight were not. [67]

In general, survivors should be counseled regarding the cardiovascular benefits of maintaining healthy weight, adhering to a heart-healthy diet, participating in regular physical activity, and abstaining from smoking. Survivors should obtain medical clearance before engaging in extreme exercise programs. Clinicians should consider baseline and follow-up screening as needed for comorbid conditions that impact cardiovascular health.

Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for cardiovascular late effects information including risk factors, evaluation, and health counseling.

Late Effects of the Central Nervous System

Neurocognitive

Neurocognitive late effects most commonly follow treatment of malignancies that require central nervous system (CNS)-directed therapies, such as cranial radiation, systemic therapy with high-dose methotrexate or cytarabine, or with intrathecal chemotherapy. Children with brain tumors or acute lymphoblastic leukemia are most likely to be affected. Risk factors for the development of neurocognitive side effects are female gender, young age at the time of treatment, higher radiation dose, and treatment with both cranial radiation and chemotherapy (systemic or intrathecal).[1][2][3][4]

Brain tumors

Survival rates have increased over recent decades for children with brain tumors; however, long-term cognitive effects due to their illness and associated treatments are emerging. In childhood and adolescent brain tumor survivors, tumor site, treatment of hydrocephalus with a shunt, paralysis, auditory difficulties, or history of a stroke have emerged as risk factors for adverse neurocognitive effects.[5][6][7]

Cranial radiation therapy has been associated with the highest risk of long-term cognitive morbidity particularly in younger children.[8] There is an established dose-response relationship with those getting higher-dose cranial radiation therapy consistently performing more poorly on intellectual measures. The negative impact of radiation treatment has been characterized by changes in intelligence quotient (IQ) scores, which have been noted to drop about 2 to 5 years after diagnosis and an attenuation of the decline 5 to 10 years afterward, followed by stabilization of the IQ scores 20 to 40 years after diagnosis.[9][10][11] The decline over time is typically reflective of the child’s failure to acquire new abilities or information at a rate similar to peers, rather than a progressive loss of skills and knowledge.[5] Affected children may experience information-processing deficits resulting in academic difficulties, and are prone to problems with receptive and expressive language, attention span, and visual and perceptual motor skills.[10][12][13] These changes in intellectual functioning may be partially explained by radiation-induced or chemotherapy-induced reduction of normal white matter volume as evaluated through magnetic resonance imaging (MRI).[14] Using lower doses of radiation and more targeted volumes have demonstrated improved results in neurocognitive effects of therapy.[7][15] In this regard, a report from St. Jude Children’s Research Hospital showed cognitive decline after conformal radiation therapy in 78 children younger than 20 years (mean, 9.7 years) with low-grade glioma treated with 54 Gy (see Figure 3). In fact, age at time of irradiation was more important than radiation dose in predicting cognitive decline. Children younger than 5 years showed the most cognitive decline.[16]

Glutathione S-transferase M1 and T1 gene polymorphisms may predict patients with medulloblastoma who are more likely to experience neurocognitive toxicity secondary to radiation.[17]

Acute lymphoblastic leukemia (ALL)

One of the great medical success stories of the past generation is how advances in the treatment of ALL have dramatically improved survival. With the recognition that CNS relapse was common among children in bone marrow remission, presymptomatic CNS radiation and intrathecal chemotherapy were introduced into the treatment of children with ALL in the 1960s and 1970s. The increase in cure rates for children with ALL over the past decades has resulted in greater attention to the neurocognitive morbidity and quality of life of survivors. The goal of current ALL treatment is to minimize adverse late effects while maintaining high survival rates. Patients are stratified for treatment according to their risk of relapse. Cranial radiation is reserved for children (less than 20%) considered at high risk for CNS relapse.[18]

Although low-, standard- and most high-risk patients currently are treated with chemotherapy-only protocols, the described neurocognitive effects for ALL patients are based on a heterogeneous treatment group of survivors in the past who were treated with combinations (simultaneously or sequentially) of intrathecal chemotherapy, radiation, and high-dose chemotherapy making it difficult to differentiate the impact of the individual components. In the future, more accurate data will be available as to the neurocognitive effects on survivors of childhood ALL treated with chemotherapy only.

In a large prospective study (N = 555) of neurocognitive outcomes in children with newly diagnosed ALL randomly assigned to CNS-directed therapy according to risk group (low: intrathecal methotrexate vs. high-dose methotrexate; high: high-dose methotrexate vs. cranial radiation therapy), a significant reduction in IQ scores (4 to 7 points) was observed between all patient groups when compared with controls (P < .002), regardless of the CNS treatment delivered. Children younger than 5 years were more likely to have IQs below 80 at 3 years compared with children older than 5 years at diagnosis, irrespective of treatment allocation, suggesting that younger children are more vulnerable to treatment-related neurologic toxic effects.[19]

In the St. Jude Total XV (NCT00137111) trial, which omitted prophylactic cranial irradiation, comprehensive cognitive testing of 243 participants at week 120 revealed higher risk for below-average performance on a measure of sustained attention, but not on measures of intellectual functioning, academic skills, or memory. The risk of cognitive deficits correlated with treatment intensity but not with age at diagnosis or gender. These results underscore the need for longitudinal follow-up to better characterize the prevalence and magnitude of cognitive deficits following CNS-directed therapy with chemotherapy alone.[20]

ALL and cranial radiation

In survivors of ALL, cranial radiation therapy does lead to identifiable neurodevelopment late sequelae. Although these abnormalities are mild in some patients (overall IQ fall of approximately 10 points), those who have received higher doses at a young age may have significant learning difficulties.[21][22] Deficits in neuropsychological functions, such as visual-motor integration, processing speed, attention, and short-term memory are reported in children treated with 1800 cGy to 2400 cGy.[23][24] Girls and younger children are more vulnerable to cranial irradiation.[25][26][27] The decline in intellectual functioning appears to be progressive, showing more impairment of cognitive function with increasing time since radiation therapy.[28] When the neurocognitive outcome of radiation therapy and chemotherapy-only CNS regimens are directly compared, the evidence suggests a better outcome for those treated with chemotherapy alone although some studies show no significant difference.[29][30][31]

It should be noted that the phenotype of attention problems in ALL survivors appears to differ from developmental attention-deficit disorder, as few survivors demonstrate significant hyperactivity/impulsivity. By contrast, impairments in cognitive efficiency (information processing and short-term memory) and executive functioning (organization and planning) have been more often observed among ALL survivors treated with cranial radiation therapy, and have been observed in children at lower frequency among those treated with chemotherapy alone.[32]

ALL and chemotherapy–only CNS therapy

Most studies of chemotherapy-only CNS-directed treatment display good neurocognitive long-term outcomes. However, one review suggests modest effects on processes of attention, speed of information processing, memory, verbal comprehension, visual-spatial skills, and visual-motor functioning; global intellectual function was found to be preserved.[23][29][33][34][35] Few longitudinal studies evaluating long-term neurocognitive outcome report adequate data for a decline in global IQ after treatment with chemotherapy alone.[34][36] The academic achievement of ALL survivors in the long term seems to be generally average for reading and spelling with deficits mainly affecting arithmetic performance.[29][37][38] Further risk factors for poor neurocognitive outcome after chemotherapy-only CNS-directed treatment are younger age and female gender.[36][39] Time since diagnosis or treatment does not appear to have a similar influence on neurocognitive functioning as observed following cranial irradiation.

Because of its penetrance into the CNS, systemic methotrexate has been used in a variety of low-dose and high-dose regimens for leukemia CNS prophylaxis. Systemic methotrexate in high doses and combined with radiation therapy can lead to an infrequent but well-described leukoencephalopathy, in which severe neurocognitive deficits are obvious.[40]

Other factors

The type of steroid used for ALL systemic treatment does not affect cognitive functioning. This is based on long-term neurocognitive testing in 92 children with a history of standard-risk ALL who had received either dexamethasone or prednisone during treatment that observed no meaningful differences in cognitive functioning based on corticosteroid randomization.[41]

Treatment intensity and duration can also adversely affect cognitive performance, because of absences from school and interruption of studies. In the Childhood Cancer Survivor Study (CCSS), treatment-related neurocognitive impairment resulted in decreased educational attainment and greater utilization of special education services. Those ALL survivors who were provided with special educational services had comparable educational attainment to siblings, whereas those not reporting use of special education had lower educational attainment.[42]

Infants with ALL

Infants with ALL are considered to be at high risk for CNS disease. In the past, infants diagnosed before age 2 years were treated with cranial irradiation. As a result, significant deficits in overall intellectual function were noted as compared with cancer controls.[43] Currently, most ALL treatment protocols do not specify cranial irradiation for infants or very young children. When cranial radiation is avoided, neurodevelopmental outcome improves. One long-term study of infants who received high-dose systemic methotrexate combined with intrathecal cytarabine and methotrexate for CNS leukemia prophylaxis and were tested 3 to 9 years posttreatment showed cognitive function was in the average range.[44]

Other cancers

Neurocognitive abnormalities have been reported in other groups of cancer survivors besides patients with CNS tumors and ALL. In a study of adult survivors of childhood non-CNS cancers (including ALL, n = 5,937), 13% to 21% of survivors had impairment in task efficiency, organization, memory, or emotional regulation. This rate of impairment was approximately 50% higher than that in the sibling comparison. Factors such as diagnosis before age 6 years, female gender, cranial radiation therapy, and hearing impediment were associated with impairment.[24]

Stem cell transplantation

Cognitive and academic consequences of stem cell transplantation in children have also been evaluated. In a report from the St. Jude Children’s Research Hospital in which 268 patients were treated with stem cell transplant, minimal risk of late cognitive and academic sequelae was seen. Subgroups of patients were at relatively higher risk, including those undergoing unrelated donor transplantation, receiving total-body irradiation, and developing graft-versus-host disease (GVHD). However, these differences were small relative to differences in premorbid functioning, particularly those associated with socioeconomic status.[45]

Neurocognitive function of pediatric patients with hematologic malignancies who had undergone hematopoietic stem cell transplantation (HSCT) was evaluated prior to HSCT and then at 1, 3, and 5 years post-HSCT. In this series of 38 patients who had all received intrathecal chemotherapy as part of their treatment, significant declines in visual motor skills and memory test scores were noted within the first year posttransplant. By 3 years posttransplant, there was an improvement in the visual motor development scores and memory scores, but there were new deficits seen in long-term memory scores. By 5 years posttransplant, there were progressive declines in verbal skills, performance skills, and new deficits seen in long-term verbal memory scores. The greatest decline in neurocognitive function occurred in patients who received cranial irradiation either as part of their initial therapy or as part of their HSCT conditioning.[46]

Most neurocognitive late effects are thought to be related to white matter damage in the brain. This was investigated in children with leukemia who were treated with HSCT. In a series of 36 patients, performance on neurocognitive measures associated with white matter was compared with performance on measures associated with gray matter. Composite white matter scores were significantly lower than composite gray matter scores.[47]

Neurologic Sequelae

Neurologic complications may be predisposed by tumor location, neurosurgery, radiation therapy, or specific neurotoxic chemotherapeutic agents. In children with CNS tumors, mass effect, tumor infiltration, and increased intracranial pressure may result in motor or sensory deficits, cerebellar dysfunction, and such secondary effects as seizures and cerebrovascular complications.

Clinical or radiographic leukoencephalopathy has been reported after cranial irradiation and high-dose systemic methotrexate administration. Younger patients and those given radiation doses greater than 24 Gy are more vulnerable to this complication. White matter changes may be accompanied by such neuroimaging abnormalities as dystrophic calcifications, cerebral lacunae, and cerebral atrophy.

Vinca alkaloid agents (vincristine and vinblastine) and cisplatin may cause peripheral neuropathy. This condition presents during treatment and appears to clinically resolve after completion of therapy. However, higher cumulative doses of vincristine and/or intrathecal methotrexate have been linked to neuromuscular impairments in long-term survivors of childhood ALL, which suggests that persistent effects of these agents may impact functional status in aging survivors.[48]

In a report from the CCSS that compared 4,151 adult survivors of childhood ALL with their siblings, survivors were at an elevated risk for late-onset coordination problems, motor problems, seizures, and headaches. The overall cumulative incidence was 44% at 20 years. Serious headaches were most common, with a cumulative incidence of 25.8% at 20 years followed by focal neurologic dysfunction (21.2%) and seizures (7%). Children who were treated with regimens that included cranial radiation for ALL and those who suffer relapse were at increased risk for late-onset neurologic sequelae.[49]

Psychosocial

Many childhood cancer survivors have adverse quality of life or other adverse psychological outcomes. Incorporation of psychological screening into clinical visits for childhood cancer survivors may be valuable; however, limiting such evaluations to those returning to long-term follow-up clinics may result in a biased subsample of those with more difficulties, and precise prevalence rates may be difficult to establish. A review of behavioral, emotional, and social adjustment among survivors of childhood brain tumors illustrates this point, in whom rates of psychological maladjustment range from 25% to 93%.[50] In a series of CNS malignancy survivors (n = 802) reported from the CCSS, adverse outcome indicators of successful adult adaptation (educational attainment, income, employment, and marital status) were most likely in survivors who report neurocognitive dysfunction.[4] Collectively, studies evaluating psychosocial outcomes among CNS tumor survivors indicate deficits in social competence in the level of social adjustment that worsen over time.[51] In a CCSS study evaluating predictors of independent living status across diagnostic groups, adult survivors of childhood cancer with neurocognitive, psychological, or physical late effects were less likely to live independently as adults compared with a sibling control group.[52] The presence of chronic health conditions can also impact other aspects of psychological health. In a study evaluating psychological outcomes among long-term survivors treated with hematopoietic cell transplantation (HCT), 22% of survivors reported adverse outcomes compared with 8% of sibling controls. Somatic distress was the most prevalent among the domains studied and affected 15% of HCT survivors, representing a threefold higher risk compared with siblings. HCT survivors with severe/life-threatening conditions and active chronic GVHD had a twofold increased risk for somatic distress.[53]

The CCSS has shown that adolescents who are long-term survivors of childhood cancer demonstrate significantly higher rates of inattention, social withdrawal, emotional problems, and externalizing problems compared with their siblings. Social withdrawal was associated with adult obesity and physical inactivity. As a result, these psychological problems may increase future risk for chronic health conditions and subsequent neoplasms and support the need to routinely screen and treat psychological problems following cancer therapy.[54] In a study of 101 adult cancer survivors of childhood cancer, psychological screening was performed during a routine annual evaluation at the survivorship clinic at the Dana Farber Cancer Institute. On the Symptom Checklist 90 Revised, 32 subjects had a positive screen (indicating psychological distress), and 14 subjects reported at least one suicidal symptom. Risk factors for psychological distress included subjects’ dissatisfaction with physical appearance, poor physical health, and treatment with cranial radiation. In this study, the instrument was shown to be feasible in the setting of a clinic visit because the psychological screening was completed in less than 30 minutes. In addition, completion of the instrument itself did not appear to result in distress on the part on the survivors in 80% of cases.[55] These data support the feasibility and importance of consistent assessment of psychosocial distress in a medical clinic setting. However, further study is needed to evaluate the true prevalence of suicidality among a representative cohort of long-term childhood cancer survivors. (Refer to the PDQ summary on Adjustment to Cancer: Anxiety and Distress for more information about psychological distress and cancer patients.)

Post-traumatic stress after childhood cancer

Despite the many stresses associated with the diagnosis of cancer and its treatment, studies have generally shown low levels of post-traumatic stress symptoms and post-traumatic stress disorder (PTSD) in children with cancer, typically no higher than healthy comparison children. Patient and parent adaptive style are significant determinants of PTSD in the pediatric oncology setting.[56][57]

The incidence of PTSD and post-traumatic stress symptoms has been reported in 15% to 20% of young adult survivors of childhood cancer, with prevalence varying based on criteria used to define these conditions.[58] Survivors with PTSD reported more psychological problems and negative beliefs about their illness and health status than those without PTSD.[59][60] A subset of adult survivors (9%) from the CCSS reported functional impairment and/or clinical distress in addition to the set of symptoms consistent with a full diagnosis of PTSD significantly more frequently than sibling control subjects.[61] In this study, PTSD was significantly associated with being unmarried, having an annual income of less than $20,000, being unemployed, having a high school education or less, and being older than 30 years. Survivors who underwent cranial radiation therapy at younger than 4 years were at particularly high risk for PTSD. Intensive treatment was also associated with increased risk of full PTSD.

Because avoidance of places and persons associated with the cancer is part of PTSD, the syndrome may interfere with obtaining appropriate health care. Those with PTSD perceived greater current threats to their lives or the lives of their children. Other risk factors include poor family functioning, decreased social support, and noncancer stressors.[62] (Refer to the PDQ summary on Post-traumatic Stress Disorder for more information about PTSD in cancer patients.)

Psychosocial outcomes among adolescent cancer survivors

Most research on late effects after cancer has focused on individuals with a cancer manifestation during childhood. Little is known about the specific impact of a cancer diagnosis with an onset in adolescence. In 820 survivors of cancer during adolescence (diagnosed between ages 15–18 years), when compared with an age-matched sample from the general population and a control group of adults without cancer, female survivors of adolescent cancers had achieved fewer developmental milestones in their psychosexual development, such as having their first boyfriend, or reached these milestones later. Male survivors were more likely to live with their parents when compared with same-sex controls. Adolescent cancer survivors were less likely to have ever married or had children. Compared with their age-matched samples, survivors were significantly older at their first marriage and at the birth of their first child.[63] Survivors in this cohort were also significantly less satisfied with their general and health-related life compared with a community-based control group. Impaired general and health-related life satisfaction were associated with somatic late effects, symptoms of depression and anxiety, and lower rates of post-traumatic growth.[64]

In a survey of 4,054 adolescent and young adult (AYA) cancer survivors and 345,592 respondents who had no history of cancer, AYA cancer survivors were more likely to smoke (26% vs. 18%), be obese (31% vs. 27%), and have chronic conditions including cardiovascular disease (14% vs. 7%), hypertension (35% vs. 9%), asthma (15% vs. 8%), disability (36% vs. 18%), and poor mental health (20% vs. 10%). They were also less likely to be receiving medical care because of cost (24% vs. 15%).[65]

The CCSS evaluated outcomes of 2,979 adolescent survivors and 649 siblings of cancer survivors to determine the incidence of difficulty in six behavioral and social domains (depression/anxiety, being headstrong, attention deficit, peer conflict/social withdrawal, antisocial behaviors, and social competence).[66] Survivors were 1.5 times (99% confidence interval [CI], 1.1–2.1) more likely than siblings to have symptoms of depression/anxiety and 1.7 times (99% CI, 1.3–2.2) more likely to have antisocial behaviors. Compared with siblings, scores in the depression/anxiety, attention deficit, and antisocial domains were significantly elevated in adolescents treated for leukemia or CNS tumors. In addition, survivors of neuroblastoma had difficulty in the depression/anxiety and antisocial domains. CNS-directed treatments (cranial radiation and/or intrathecal methotrexate) were specific risk factors for adverse behavioral outcomes.

Because of the challenges associated with the diagnosis of an AYA cancer, it is important for this group to have access to programs to address the unique psychosocial, educational, and vocational issues that impact their transition to survivorship.[67][68]

Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for CNS and psychosocial late effects information including risk factors, evaluation, and health counseling.

Late Effects of the Digestive System

Dental

Both chemotherapy and radiation therapy can cause multiple cosmetic and functional abnormalities of dentition, most predominantly in children treated before age 5 years who have not yet developed deciduous dentition.[1][2][3][4][5][6][7][8][9] However, even older prepubertal children are at risk. Developing teeth are irradiated in the course of treating head and neck sarcomas, Hodgkin lymphoma, neuroblastoma, central nervous system leukemia, nasopharyngeal cancer, and as a component of total-body irradiation (TBI). Doses of 20 Gy to 40 Gy can cause root shortening or abnormal curvature, dwarfism, and hypocalcification.[10] More than 85% of survivors of head and neck rhabdomyosarcoma who receive radiation doses greater than 40 Gy may have significant dental abnormalities, including mandibular or maxillary hypoplasia, increased caries, hypodontia, microdontia, root stunting, and xerostomia.[6][7]

Chemotherapy for the treatment of leukemia can cause shortening and thinning of the premolar roots and enamel abnormalities.[1][11][12] Childhood Cancer Survivor Study investigators identified age younger than 5 years and increased exposure to cyclophosphamide as significant risk factors for developmental dental abnormalities in long-term survivors of childhood cancer.[4] TBI has been linked to the development of short, V-shaped roots, microdontia, enamel hypoplasia, and premature apical closure.[2][3][13] The younger a patient is when treated with hematopoietic stem cell transplantation (HSCT), the more severely disturbed dental development will be and the more deficient vertical growth of the lower face will be. In children who have undergone HSCT, busulfan has been as deleterious to dental development and craniofacial growth as single-dose TBI.[14] Children who undergo bone marrow transplantation with TBI for neuroblastoma are at substantial risk for a spectrum of abnormalities and require close surveillance and appropriate interventions.[15]

Salivary gland irradiation incidental to treatment of head and neck malignancies or Hodgkin lymphoma causes a qualitative and quantitative change in salivary flow, which can be reversible after doses of less than 40 Gy but may be irreversible after higher doses, depending on whether sensitizing chemotherapy is also administered.[16] Dental caries are the most problematic consequence. The use of topical fluoride can dramatically reduce the frequency of caries, and saliva substitutes and sialagogues can ameliorate sequelae such as xerostomia.[17]

It has been reported that the incidence of dental visits for childhood cancer survivors falls below the American Dental Association's recommendation that all adults visit the dentist annually.[18] These findings give health care providers further impetus to encourage routine dental and dental hygiene evaluations for survivors of childhood treatment. (Refer to the PDQ summary on Oral Complications of Chemotherapy and Head/Neck Radiation for more information about oral complications and cancer patients.)

Digestive Tract

Radiation and specific chemotherapeutic agents may produce gastrointestinal (GI) or hepatic toxicity that is acute and transient in the majority of patients, but rarely may be delayed and persistent. Late radiation injury to the digestive tract is attributable to vascular injury. Necrosis, ulceration, stenosis, or perforation can occur and are characterized by malabsorption, pain, and recurrent episodes of bowel obstruction, as well as perforation and infection.[19][20][21] In general, fractionated doses of 20 Gy to 30 Gy can be delivered to the small bowel without significant long-term morbidity. Doses greater than 40 Gy cause bowel obstruction or chronic enterocolitis.[22] Sensitizing chemotherapeutic agents such as dactinomycin or anthracyclines can increase this risk.

A limited number of reports describe GI complications in pediatric patients with genitourinary solid tumors treated with radiation.[23][24][25][26][27] One study comprehensively evaluated intestinal symptoms in 44 children with cancer who underwent whole-abdominal (10 Gy to 40 Gy) and involved-field (25 Gy to 40 Gy) radiation and received additional interventions predisposing them to GI tract complications including abdominal laparotomy in 43 (98%) and chemotherapy in 25 (57%) patients.[23] Late small bowel obstruction was observed in 36% of patients surviving 19 months to 7 years, which was uniformly preceded by small bowel toxicity during therapy. Reports from the Intergroup Rhabdomyosarcoma Study evaluating GI toxicity in long-term survivors of genitourinary rhabdomyosarcoma infrequently observed abnormalities of the irradiated bowel.[24][25][27] Radiation-related complications occurred in approximately 10% of long-term survivors of paratesticular and bladder/prostate rhabdomyosarcoma and included intraperitoneal adhesions with bowel obstruction, chronic diarrhea, and stricture or enteric fistula formation.[24][27] Children irradiated at lower doses for Wilms tumor also uncommonly develop chronic GI toxicity. Several studies have reported cases of small bowel obstruction following abdominal surgery, but the role of radiation appears to be less important as operative findings of enteritis have not consistently been observed.[26][28] Among 5-year childhood cancer survivors participating in the Childhood Cancer Survivor Study (CCSS), the cumulative incidence of self-reported GI conditions was 37.6% at 20 years (25.8% for upper GI complications and 15.5% for lower GI complications) from cancer diagnosis representing an almost twofold excess risk of upper GI (relative risk [RR] = 1.8; 95% confidence interval [CI], 1.6–2.0) and lower GI (RR = 1.9; 95% CI, 1.7–2.2) complications compared with sibling controls. Factors predicting higher risk of specific GI complications include older age at diagnosis, intensified therapy (anthracyclines for upper GI complications and alkylating agents for lower GI complications), abdominal radiation, and abdominal surgery.[29]

Hepatobiliary

Hepatic complications resulting from childhood cancer therapy are uncommon and observed primarily as acute treatment toxicities.[30] Recipients of HSCT are the exception to this rule as these individuals frequently experience chronic liver dysfunction related to microvascular, immunologic, infectious, metabolic, and toxic etiologies. Chemotherapeutic agents with established hepatotoxic potential include antimetabolite agents like 6-mercaptopurine, 6-thioguanine, methotrexate, and rarely, dactinomycin. Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) and cholestatic disease have been observed after thiopurine administration, especially 6-thioguanine. Progressive fibrosis and portal hypertension has been reported in a subset of children who developed VOD/SOS following treatment with 6-thioguanine.[31][32][33] Acute, dose-related, reversible VOD/SOS has been observed in children treated with dactinomycin for pediatric solid tumors.[34][35] In the transplant setting, VOD/SOS has also been observed following conditioning regimens that have included cyclophosphamide/TBI, busulfan/cyclophosphamide and carmustine/cyclophosphamide/etoposide.[36] Because high-dose cyclophosphamide is common to all of these regimens, toxic cyclophosphamide metabolites resulting from the agent’s variable metabolism have been speculated as a causative factor.

Acute radiation-induced liver disease also causes endothelial cell injury that is characteristic of VOD/SOS.[37] In adults, the whole liver has tolerance up to 30 Gy to 35 Gy with conventional fractionation, the prevalence of radiation-induced liver disease varies from 6% to 66% based on the volume of liver involved and on hepatic reserve.[37][38] Based on limited data from pediatric cohorts treated in the 1970s and 1980s, persistent radiation hepatopathy after contemporary treatment appears to be uncommon in long-term survivors without predisposing conditions such as viral hepatitis or iron overload.[39] The risk of injury in children increases with radiation dose, hepatic volume, younger age at treatment, prior partial hepatectomy, and concomitant use of radiomimetic chemotherapy like dactinomycin and doxorubicin.[40][41][42][43] Survivors who received radiation doses of 40 Gy to at least one-third of liver volume, doses of 30 Gy or more to whole abdomen, or an upper abdominal field involving the entire liver are at highest risk for hepatic dysfunction.[44]

Viral hepatitis B and C may complicate the treatment course of childhood cancer and result in chronic hepatic dysfunction. Hepatitis B tends to have a more aggressive acute clinical course and a lower rate of chronic infection. Hepatitis C is characterized by a mild acute infection and a high rate of chronic infection. The incidence of transfusion-related hepatitis C in childhood cancer survivors has ranged from 5% to 50% depending on the geographic location of the reporting center.[45][46][47][48][49][50][51] Chronic hepatitis predisposes cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Concurrent infection with both viruses accelerates the progression of liver disease. Since the majority of patients received some type of blood product during childhood cancer treatment and many are unaware of their transfusion history, screening based on date of diagnosis/treatment is recommended unless there is absolute certainty that the patient did not receive any blood or blood products.[52] Therefore, all children who received blood transfusions before 1972 should be screened for hepatitis B and before 1993 should be screened for hepatitis C virus and referred for discussion of treatment options.

Less commonly reported hepatobiliary complications include cholelithiasis, focal nodular hyperplasia, nodular regenerative hyperplasia, and microvesicular fatty change. In limited studies, an increased risk of cholelithiasis has been linked to ileal conduit, parenteral nutrition, abdominal surgery, abdominal radiation, and HSCT.[53][54] Gallbladder disease was the most frequent late-onset liver condition reported among participants in the CCSS and they had a twofold excess risk compared with sibling controls (RR = 2.0; 95% CI, 2.0–40.0).[29] Lesions made up of regenerating liver called focal nodular hyperplasia have been incidentally noted after chemotherapy or HSCT.[55][56] These lesions are thought to be iatrogenic manifestations of vascular damage and have been associated with VOD, high-dose alkylating agents (e.g., busulfan and melphalan), and liver radiation therapy. The prevalence of this finding is unknown, noted at less than 1% in some papers;[56] however, this is likely an underestimate. In one study of patients who were followed by magnetic resonance imaging (MRI) after transplant to assess liver iron stores, the cumulative incidence was 35% at 150 months posttransplant.[55] The lesions can mimic metastatic or subsequent tumors, but MRI imaging is generally diagnostic, and unless the lesions grow or patients have worrisome symptoms, biopsy or resection is generally not necessary.

Nodular
regenerative hyperplasia is a rare condition characterized by the development of multiple monoacinar regenerative hepatic nodules and mild fibrosis. The pathogenesis is not well established, but may represent a nonspecific tissue adaptation to heterogeneous hepatic blood flow.[57]
Nodular
regenerative hyperplasia has rarely been observed in survivors of childhood cancer treated with chemotherapy, with or without liver radiation therapy.[58][59] Biopsy may be necessary to distinguish nodular
regenerative hyperplasia from a subsequent malignancy.

In a cohort who recently completed intensified therapy for acute lymphoblastic leukemia, histologic evidence of fatty infiltration was noted in 93% and siderosis in up to 70% of patients.[60] Fibrosis developed in 11% and was associated with higher serum low-density lipoprotein (LDL) cholesterol. Fatty liver with insulin resistance has also been reported to develop more frequently in long-term childhood cancer survivors treated with cranial radiation before allogeneic stem cell transplantation who were not overweight or obese.[61] Prospective studies are needed to define whether acute posttherapy fatty liver change contributes to the development of steatohepatitis or the metabolic syndrome in this population. Likewise, information about the long-term outcomes of transfusion-related iron overload is lacking, especially among survivor cohorts who did not undergo hematopoietic cell transplantation.

Survivors with liver dysfunction should be counseled regarding risk-reduction methods to prevent hepatic injury. Standard recommendations include maintenance of a healthy body weight, abstinence from alcohol use, and immunization against hepatitis A and B viruses. In patients with chronic hepatitis, precautions to reduce viral transmission to household and sexual contacts should also be reviewed.

Pancreas

The pancreas has been thought to be relatively radioresistant because of a paucity of information about late pancreatic-related effects. However, children and young adults treated with total-body or abdominal radiation are known to have an increased risk of insulin resistance and diabetes mellitus.

A retrospective cohort study, based on self-reports of 2,520 five-year survivors of childhood cancer treated in France and the United Kingdom, investigated the relationship between radiation dose to the pancreas and risk of a subsequent diabetes diagnosis. Sixty-five cases of diabetes were validated; the risk increased with radiation to the tail of the pancreas, where the islets of Langerhans are concentrated. Risk increased up to 20 to 29 Gy and then plateaued. The estimated RR at 1 Gy was 1.61. Radiation dose to other parts of the pancreas did not have a significant effect. Compared with patients who did not receive radiation, the RR of diabetes was 11.5 in patients who received more than 10 Gy to the pancreas. Children younger than 2 years at the time of radiation were more sensitive than older patients (RR at 1 Gy was 2.1 for the young age group vs. 1.4 for older patients). For the 511 patients who received more than 10 Gy, the cumulative incidence of diabetes was 16%.[62]

Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for digestive system late effects information including risk factors, evaluation, and health counseling.

Late Effects of the Endocrine System

Thyroid Gland

Thyroid dysfunction, manifested by primary hypothyroidism, hyperthyroidism, goiter, or nodules, is a common delayed effect of radiation therapy fields that include the thyroid gland incidental to treating Hodgkin lymphoma (HL), brain tumors, head and neck sarcomas, and acute lymphoblastic leukemia.

Hypothyroidism

Of children treated with radiation therapy, most develop hypothyroidism within the first 2 to 5 years posttreatment, but new cases can occur later. Reports of thyroid dysfunction differ depending on the dose of radiation, the length of follow-up, and the biochemical criteria utilized to make the diagnosis.[1] The most frequently reported abnormalities include elevated thyroid-stimulating hormone (TSH), depressed thyroxine (T4), or both.[2][3][4][5] Compensated hypothyroidism includes an elevated TSH with a normal T4 and is asymptomatic. The natural history is unclear, but most endocrinologists support treatment. Uncompensated hypothyroidism includes both an elevated TSH and a depressed T4. Thyroid hormone replacement is beneficial for correction of the metabolic abnormality, and has clinical benefits for cardiovascular, gastrointestinal, and neurocognitive function.

The incidence of hypothyroidism should decrease with lower cumulative doses of radiation therapy employed in newer protocols. In a study of 1,677 children and adults with HL who were treated with radiation therapy between 1961 and 1989, the actuarial risk at 26 years posttreatment for overt or subclinical hypothyroidism was 47%, with a peak incidence at 2 to 3 years posttreatment.[6] In a study of HL patients treated between 1962 and 1979, hypothyroidism occurred in 4 of 24 patients who received mantle doses less than 26 Gy but in 74 of 95 patients who received greater than 26 Gy. The peak incidence occurred at 3 to 5 years posttreatment, with a median of 4.6 years.[7] A cohort of childhood HL survivors treated between 1970 and 1986 were evaluated for thyroid disease by use of a self-report questionnaire in the Childhood Cancer Survivor Study (CCSS). Among 1,791 survivors, 34% reported that they had been diagnosed with at least one thyroid abnormality. For hypothyroidism, there was a clear dose response, with a 20-year risk of 20% for those who received less than 35 Gy, 30% for those who received 35 Gy to 44.9 Gy, and 50% for those who received greater than 45 Gy to the thyroid gland. The relative risk (RR) for hypothyroidism was 17.1; for hyperthyroidism 8.0; and for thyroid nodules, 27.0. Elapsed time since diagnosis was a risk factor for both hypothyroidism and hyperthyroidism, where the risk increased in the first 3 to 5 years after diagnosis. For nodules, the risk increased beginning at 10 years after diagnosis. Females were at increased risk for hypothyroidism and thyroid nodules.[8]

As might be expected, children treated for head and neck malignancies are also at risk for primary hypothyroidism if the neck is irradiated. The German Group of Paediatric Radiation Oncology reported on 1,086 patients treated at 62 centers, including 404 patients (median age, 10.9 years) who had received radiation therapy to the thyroid gland and/or hypophysis. Follow-up information was available for 264 patients (60.9%; median follow-up, 40 months), with 60 patients (22.7%) showing pathologic values. In comparison to patients treated with prophylactic cranial irradiation (median dose, 12 Gy), patients with radiation doses of 15 Gy to 25 Gy to the thyroid gland had a hazard ratio (HR) of 3.072 (P = .002) for the development of pathologic thyroid blood values. Patients with greater than 25 Gy to the thyroid gland and patients who underwent craniospinal irradiation had HR of 3.768 (P = .009) and 5.674 (P < .001), respectively. The cumulative incidence of thyroid hormone substitution therapy did not differ between defined subgroups.[9]

Thyroid nodules

Any radiation field that includes the thyroid is associated with an excess risk of thyroid neoplasms, which may be benign (usually adenomas) or malignant (most often differentiated papillary carcinoma).[8][10][11][12][13] The clinical manifestation of thyroid neoplasia among childhood cancer survivors ranges from asymptomatic, small, solitary nodules to large, intrathoracic goiters that compress adjacent structures. The risk of thyroid nodule development increases with increasing time from radiation exposure. In a study of Hodgkin lymphoma survivors, CCSS investigators identified time from diagnosis, female gender, and radiation dose of 25 Gy or more as significant risk factors for thyroid nodule development.[8] Based on a cohort of 3,254 two-year childhood cancer survivors treated before 1986 and monitored for 25 years, the risk of thyroid adenoma increased with the size of the radiation dose to the thyroid during childhood cancer treatment and plateaued at doses exceeding 10 Gy. The risk of thyroid adenoma per unit of radiation dose to the thyroid was higher if radiation therapy had been delivered before age 5 years and before the attained age of 4 years.[11] Younger age at radiation therapy has also been linked to an excess risk of thyroid carcinoma.[10][11][12][13] An increased risk of thyroid nodules/cancer has also been observed in association with chemotherapy, independent of radiation exposure.[10][11]

During childhood and adolescence, there is an increased incidence of developing thyroid nodules, and potentially, thyroid cancer for patients exposed to iodine I 131 metaiodobenzylguanidine (131I-mIBG). Children who have been treated with 131I-mIBG should undergo lifelong monitoring, not only for thyroid function but also for the development of thyroid nodules and thyroid cancer.[14]

Several investigations have demonstrated the superiority of ultrasound to clinical exam for detecting thyroid nodules/cancers and characterized ultrasonographic features of nodules that are more likely to be malignant.[15][16] However, primary screening for thyroid neoplasia (beyond physical exam with thyroid palpation) remains controversial because of the lack of data indicating a survival benefit and quality-of-life benefit associated with early detection and intervention. In fact, because these lesions tend to be indolent, are rarely life-threatening, and may clinically manifest many years after exposure to radiation, there are significant concerns regarding the costs and harms of overscreening.[17]

(Refer to the Subsequent Neoplasms section of this summary for information about subsequent thyroid cancers.)

Posttransplant thyroid dysfunction

Survivors of pediatric hematopoietic stem cell transplant are at increased risk of thyroid dysfunction, with the risk being much lower (15%–16%) after fractionated total-body irradiation (TBI), as opposed to single-dose TBI (46%–48%). Non–TBI-containing regimens historically were not associated with an increased risk. However, in a report from the Fred Hutchinson Cancer Research Center, the increased risk of thyroid dysfunction was not different between children receiving a TBI or busulfan-based regimen (P = .48).[18] Other high-dose therapies have not been studied. While mildly elevated TSH is common, it is usually accompanied by normal thyroxine concentration.[19][20]

Central hypothyroidism is discussed with late effects that affect the pituitary gland.

Pituitary Gland

Survivors of childhood cancer are at risk for a spectrum of neuroendocrine abnormalities, primarily due to the effect of radiation therapy on the hypothalamus. Essentially all of the hypothalamic-pituitary axes are at risk.[21][22][23] The six anterior pituitary hormones and their major hypothalamic regulatory factors are outlined in Table 8.

Growth hormone deficiency

Growth hormone deficiency (GHD) is the first and most common side effect of cranial irradiation in brain tumor survivors. The risk increases with radiation dose and time after treatment. GHD is the earliest hormone deficiency and is sensitive to low doses. Other hormone deficiencies require higher doses and their time to onset is much longer than for GHD.[24] The prevalence in pooled analysis was found to be approximately 35.6%.[25] The potential for neuroendocrine damage is likely to decrease because of the use of more focused radiation therapy and a decrease in dose for some malignancies such as medulloblastoma.

Approximately 60% to 80% of irradiated pediatric brain tumor patients who have received doses greater than 30 Gy will have impaired serum growth hormone (GH) response to provocative stimulation, usually within 5 years of treatment. The dose-response relationship has a threshold of 18 Gy to 20 Gy; the higher the radiation dose, the earlier that GHD will occur after treatment. A study of conformal radiation therapy in children with central nervous system (CNS) tumors indicates that GH insufficiency can usually be demonstrated within 12 months of radiation therapy, depending on hypothalamic dose-volume effects.[26] In a recent report from the St. Jude Children’s Research Hospital on data from 118 patients with localized brain tumors that were treated with radiation therapy, peak GH was modeled as an exponential function of time after conformal radiation therapy (CRT) and mean radiation dose to the hypothalamus. The average patient was predicted to develop GHD with the following combinations of time after CRT and mean dose to the hypothalamus: 12 months and more than 60 Gy; 36 months and 25 Gy to 30 Gy; and 60 months and 15 Gy to 20 Gy. A cumulative dose of 16.1 Gy to the hypothalamus would be considered the mean radiation dose required to achieve a 50% risk of GHD at 5 years (TD50/5).[27]

Children treated with CNS irradiation for leukemia are also at increased risk of GHD. One study evaluated 127 patients with acute lymphocytic leukemia (ALL) treated with 24 Gy, 18 Gy, or no cranial irradiation. The change in height, compared with population norms expressed as the standard deviation score (SDS), was significant for all three groups with a dose-response of -0.49 ± 0.14 for the no radiation therapy group, -0.65 ± 0.15 for the 18 Gy radiation therapy group, and -1.38 ± 0.16 for the 24 Gy group.[28] Another study found similar results in 118 ALL survivors treated with 24 Gy cranial irradiation, in which 74% had SDS score of -1 or greater and the remainder had -2 or greater.[29] However, survivors of childhood ALL who are treated with chemotherapy alone are also at increased risk for adult short stature, though the risk is highest for those treated with cranial and craniospinal radiation therapy at a young age.[30] In this cross-sectional study, attained adult height was determined among 2,434 ALL survivors participating in the Childhood Cancer Survivor Study (CCSS). All survivor treatment exposure groups (chemotherapy alone and chemotherapy with cranial or craniospinal radiation therapy) had decreased adult height and an increased risk of adult short stature (height standard deviation score < -2) compared with siblings (P < .001). Compared with siblings, the risk of short stature for survivors treated with chemotherapy alone was elevated (odds ratio = 3.4; 95% confidence interval [CI], 1.9–6.0). Among survivors, significant risk factors for short stature included diagnosis of ALL before puberty, higher-dose cranial radiation therapy (≥20 Gy vs. <20 Gy), any radiation therapy to the spine, and female gender.

GHD has been reported in 14% of survivors of childhood nasopharyngeal carcinoma, which is secondary to the hypothalamic/pituitary radiation.[31] This incidence is likely an underestimate since screening was selective.

Children who undergo hematopoietic stem cell transplantation (HSCT) with total-body irradiation (TBI) have a significant risk of both GHD and the direct effects of radiation on skeletal development. Risk is increased with single-dose as opposed to fractionated TBI, pretransplant cranial irradiation, female gender, and posttreatment complications such as graft-versus-host disease (GVHD).[32][33][34] Regimens containing busulfan and cyclophosphamide appear to increase risk in some studies,[34][35] but not others.[36] Hyperfractionation of the TBI dose markedly reduces risk in patients who have not undergone pretransplant cranial radiation for CNS leukemia prophylaxis or therapy.[37]

The late effects that occur after HSCT have been studied and reviewed by the Late Effect Working Party of the European Group for Blood and Marrow Transplantation. Among 181 patients with aplastic anemia, leukemias, and lymphomas who underwent HSCT before puberty, an overall decrease in final height-SDS value was found compared with height at transplant and genetic height. The mean loss of height is estimated to be approximately 1 height-SDS (6 cm) compared with the mean height at time of HSCT and mean genetic height. The type of transplantation, GVHD, GH, or steroid treatment did not influence final height. TBI (single-dose radiation therapy more than fractionated-dose radiation therapy), male gender, and young age at transplant, were found to be major factors for long-term height loss. Most patients (140 of 181) reached adult height within the normal range of the general population.[38][39]

GHD should be treated with replacement therapy. Some controversy surrounds this, with a concern over increased risk of primary tumor recurrence and subsequent malignancies. Most studies, however, are limited by selection bias and small sample size. One study evaluated 361 GH-treated cancer survivors enrolled in the CCSS and compared risk of recurrence, risk of subsequent neoplasm, and risk of death among survivors who did and did not receive treatment with GH. The RR of disease recurrence was 0.83 (95% CI, 0.37–1.86) for GH-treated survivors. GH-treated subjects were diagnosed with 15 subsequent neoplasms, all solid tumors, for an overall RR of 3.21 (95% CI, 1.88–5.46), mainly because of a small excess number of subsequent neoplasms observed in survivors of acute leukemia.[40] With prolonged follow-up, the elevation of subsequent cancer risk due to GH diminished.[41] Compared with survivors not treated with GH, those who were treated had a twofold excess risk of developing a subsequent neoplasm (RR = 2.15; 95% CI, 1.33–3.47, P < .002), and meningiomas were the most commonly observed (9 of 20 tumors). A review of existing data suggests that treatment with GH is not associated with an increased risk of CNS tumor progression or recurrence, or new or recurrent leukemia.[42] In general, the data addressing subsequent malignancies should be interpreted with caution given the small number of events.[40]

Gonadal abnormalities

Pubertal development can be adversely affected by cranial radiation. Doses greater than 30 Gy to 40 Gy may result in gonadotropin deficiency, while doses greater than 18 Gy can result in precocious puberty.[43] Precocious puberty has been reported in some children receiving cranial irradiation, mostly in girls who receive cranial radiation in doses of 24 Gy or higher. Earlier puberty and earlier peak height velocity, however, have been observed in girls treated with 18 Gy cranial radiation.[44][45] Another study showed that the age of pubertal onset is positively correlated with age at the time of cranial irradiation. The impact of early puberty in a child with radiation-associated GHD is significant, and timing of GH therapy is especially important for GH-deficient females also at risk of precocious puberty.[45] With higher doses of cranial irradiation (>35 Gy), deficiencies in the gonadotropins can be seen, with a cumulative incidence of 10% to 20% at 5 to 10 years posttreatment.[46][47][48]

Hypothyroidism

Central hypothyroidism in survivors of childhood cancer can have profound clinical consequences and be underappreciated. Symptoms of central hypothyroidism (e.g., asthenia, edema, drowsiness, and skin dryness) may have a gradual onset and go unrecognized until thyroid replacement therapy is initiated. In addition to delayed puberty and slow growth, hypothyroidism may cause fatigue, dry skin, constipation, increased sleep requirement, and cold intolerance. Radiation dose to the hypothalamus in excess of 42 Gy is associated with an increase in the risk of developing thyroid-stimulating hormone (TSH) deficiency, 44% ± 19% (dose ≥42 Gy) and 11% ± 8% (dose <42 Gy).[49] It occurs in as many as 65% of survivors of brain tumors, 43% of survivors of childhood nasopharyngeal tumors, 35% of bone marrow transplant recipients, and 10% to 15% of leukemia survivors.[31][50]

Mixed primary and central hypothyroidism can also occur and reflects separate injuries to the thyroid gland and the hypothalamus (e.g., radiation injury to both structures). TSH values may be elevated and, in addition, the secretory dynamics of TSH are abnormal with a blunted or absent TSH surge or a delayed peak response to thyrotropin-releasing hormone (TRH).[22][51] In a study of 208 childhood cancer survivors referred for evaluation of possible hypothyroidism or hypopituitarism, mixed hypothyroidism was present in 15 (7%) patients.[51] Among patients who received TBI (fractionated total doses of 12 Gy–14.4 Gy) or craniospinal irradiation (fractionated total cranial doses higher than 30 Gy), 15% had mixed hypothyroidism. In one study of 32 children treated for medulloblastoma, 56% developed hypothyroidism, including 38% with primary hypothyroidism, and 19% with central hypothyroidism.[52]

Adrenal-corticotropin deficiency

Adrenocorticotropic hormone (ACTH) deficiency is less common than other neuroendocrine deficits but should be suspected in patients who have a history of brain tumor (regardless of therapy modality), cranial irradiation, GH deficiency, or central hypothyroidism.[22][24][49][53][54][55][56] Although uncommon, ACTH deficiency can occur in patients who have received intracranial radiation that did not exceed 24 Gy and has been reported to occur in less than 3% of patients after chemotherapy alone.[56] Patients with partial ACTH deficiency may have only subtle symptoms unless they become ill. Illness can disrupt these patients’ usual homeostasis and cause a more severe, prolonged, or complicated course than expected. As in complete ACTH deficiency, incomplete or unrecognized ACTH deficiency can be life-threatening during concurrent illness.

Hyperprolactinemia

Hyperprolactinemia has been described in patients who have received doses of radiation higher than 50 Gy to the hypothalamus or who have undergone surgery disrupting the integrity of the pituitary stalk. Hyperprolactinemia may result in delayed puberty. In adult women, hyperprolactinemia may cause galactorrhea, menstrual irregularities, loss of libido, hot flashes, infertility, and osteopenia; in adult men, impotence and loss of libido. Primary hypothyroidism may lead to hyperprolactinemia as a result of hyperplasia of thyrotrophs and lactotrophs, presumably due to TRH hypersecretion. The prolactin response to TRH is usually exaggerated in these patients.[22][24][53]

Testis and Ovary

Testicular and ovarian hormonal function are discussed in the Late Effects of the Reproductive System section of this summary.

Metabolic Syndrome

The metabolic syndrome is highly associated with cardiovascular events and mortality. Definitions of the metabolic syndrome are evolving, but generally include a combination of central (abdominal) obesity with at least two or more of the following features:

An increased risk of metabolic syndrome or its components has been observed among cancer survivors. Long-term survivors of ALL, especially those treated with cranial radiation, may have a higher prevalence of some, potentially modifiable, risk factors for cardiovascular disease such as impaired glucose tolerance or overt diabetes, dyslipidemia, hypertension, and obesity.[58][59][60] In a cross-sectional study comparing cardiovascular risk factors and insulin resistance among 319 childhood cancer survivors (median age, 14.5 years; median time from diagnosis, 10.1 years) and 208 sibling controls, no difference was observed in weight and body mass index (BMI), although survivors had greater adiposity, percent fat, and lower lean body mass than siblings. Childhood cancer survivors also had higher total and low-density lipoprotein (LDL) cholesterol and triglycerides and lower insulin sensitivity compared with siblings.[61] In a young adult cohort of ALL survivors (mean age 30 years), 62% had at least one cardiovascular risk factor and 30% had two or more.[62] Another study observed no difference in prevalence of metabolic syndrome in 75 ALL survivors compared with a population-based control group.[63] However, survivors with metabolic syndrome were more likely to have GH insufficiency or deficiency. Those treated with cranial radiation therapy also had an association with GH abnormalities and were more likely to have two or more components of the metabolic syndrome compared with survivors who were not treated with cranial radiation therapy.

A high frequency of cardiovascular risk factors has also been observed among hematopoietic cell transplant recipients.[64][65] French investigators reported an overall 9.2% (95% CI, 5.5–14.4) prevalence of metabolic syndrome in a cohort of 184 ALL survivors (median age 21.2 years).[66] Gender, age at diagnosis, corticosteroid therapy, or cranial radiation were not significant predictors of metabolic syndrome. However, hematopoietic cell transplantation with TBI was a major risk factor for metabolic syndrome (odds ratio [OR] = 3.9, P = .03). Other investigators have reported a significantly increased risk of hyperinsulinemia, impaired glucose tolerance, or diabetes mellitus associated with exposure to TBI.[59][67] The association between TBI and excess risk for diabetes has also been observed by other investigators.[68]
These data suggest that survivors might benefit from targeted screening and lifestyle counseling regarding risk reduction measures.

Changes in Body Composition: Obesity and Body Fatness

To date, the primary cancer groups recognized with an increased incidence of treatment-related obesity are ALL [69][70][71][72][73][74][75][76][77][78][79][80][81][82][83] and CNS tumor [21][22][84] survivors treated with cranial radiation therapy.[85][86] In addition, craniopharyngioma survivors also have a substantially increased risk of extreme obesity due to the tumor location and the hypothalamic-pituitary-adrenal (HPA) damage resulting from surgical resection.[87][88][89][90][91][92][93]

In addition to treatment factors, lifestyle factors and medication use can also contribute to the risk of obesity. CCSS investigators reported the following independent risk factors for obesity in childhood cancer survivors:[94]

Survivors who adhered to the U.S. Centers for Disease Control and Prevention guidelines for vigorous physical activity (RR, 0.90; 95% CI, 0.82–0.97; P = .01) and who had a medium amount of anxiety (RR, 0.86; 95% CI, 0.75–0.99; P = .04) had a lower risk of obesity.[94]

Moderate-dose cranial radiation therapy (18–24 Gy) among ALL survivors is associated with obesity, particularly in females treated at a young age.[60][73][79][95] Female adult survivors of childhood ALL who were treated with cranial radiation therapy of 24 Gy prior to age 5 years are four times more likely to be obese in comparison with women who have not been treated for a cancer.[73] In addition, women treated with 18 Gy to 24 Gy cranial radiation therapy prior to age 10 years have a substantially greater rate of increase in their BMI through their young adult years in comparison with women who were treated for ALL with only chemotherapy or with women in the general population.[79] It appears that these women also have a significantly increased visceral adiposity and associated insulin resistance.[96][97] These outcomes are attenuated in males. Interestingly, among brain tumor survivors treated with higher doses of cranial radiation therapy, only females treated at a younger age appear to be at increased risk for obesity.[98] The development of obesity following cranial radiation therapy is multifactorial, with factors including GHD, leptin sensitivity, reduced levels of physical activity, and energy expenditure.[79][99][100] Importantly, survivors of childhood cancer treated with TBI in preparation for an allogeneic HSCT have increased measures of body fatness (percent fat) while often having a normal BMI.[67][101]

It remains controversial whether contemporary ALL therapy, without cranial radiation therapy, is associated with a sustained increase in BMI. During and soon after completion of therapy, there appears to be an increase in BMI z-scores among children treated for ALL with only chemotherapy.[80][81][82][102] However, investigators from the CCSS did not find a significant association among adult survivors of childhood ALL between chemotherapy-only protocols and risk of obesity or change in BMI over time. Notably, while there may not be an increased incidence of obesity, as measured by BMI, among adult survivors of childhood ALL, there does appear to be an increase in percent body fat [78][83][97][103] and visceral adiposity.[96]

Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for endocrine and metabolic syndrome late effects information including risk factors, evaluation, and health counseling.

Late Effects of the Immune System

Spleen

Surgical or functional splenectomy increases risk of life-threatening invasive bacterial infection.[1] Although staging laparotomy is no longer standard practice for pediatric Hodgkin lymphoma, patients from earlier time periods have ongoing risks.[2][3] In addition, children may be rendered asplenic by radiation therapy to the spleen in doses greater than 30 Gy.[4][5] Low-dose involved-field radiation (21 Gy) combined with multiagent chemotherapy did not appear to adversely affect splenic function as measured by pitted red blood cell assays.[5] No other studies of immune status after radiation therapy are available. Functional asplenia (with Howell Jolly bodies, reduced splenic size and blood flow) after bone marrow transplantation has been attributed to graft-versus-host disease (GVHD).

A pneumococcal vaccine booster is recommended for patients aged 10 years and older and more than 5 years after previous dose.[6] Asplenic patients should also be immunized against Neisseria meningitidis and Haemophilus influenzae type B and should receive antibiotic prophylaxis for dental work.

Prophylactic antibiotics (penicillin or similar broad-spectrum agent) have been recommended for at least 2 to 3 years after splenectomy and until at least 5 years of age for young children.[7] Randomized studies that address the benefit of daily prophylactic antibiotics have not been conducted in a pediatric oncology population; thus, these recommendations are based on extrapolated study data derived from other populations with asplenia.[8][9][10][11] The benefit of prolonged antibiotic prophylaxis is also unknown. Many patients, over time, discontinue use of penicillin; consideration should be given to ensuring availability of appropriate antibiotics for use at the first onset of febrile illness in patients who are not on daily prophylaxis. Medical care should be sought promptly for fevers higher than 38.5°C.

Refer to the Centers for Disease Control and Prevention (CDC) Guidelines for Preventing Opportunistic Infections Among Hematopoietic Stem Cell Transplant Recipients for more information on posttransplant immunization.

Immune System

Although the immune system appears to recover from the effects of active chemotherapy and radiation, there is some evidence that lymphoid subsets may not always normalize. Innate immunity, thymopoiesis, and DNA damage responses to radiation were shown to be abnormal in survivors of childhood leukemia.[12] Antibody levels to previous vaccinations are also reduced in patients off therapy for acute lymphoblastic leukemia for at least one year,[13][14] suggesting persistence of abnormal humoral immunity [15] and a need for revaccination in such children. Immune status is also compromised after stem cell transplantation, particularly in association with GVHD.[16] In a prospective, longitudinal study of 210 survivors treated with allogeneic hematopoietic cell transplantation, antibody responses lasting for more than 5 years after immunization were observed in most patients for tetanus (95.7%), rubella (92.3%), poliovirus (97.9%), and, in diphtheria-tetanus-acellular pertussis (DTaP) recipients, diphtheria (100%) . However, responses to pertussis (25.0%), measles (66.7%), mumps (61.5%), hepatitis B (72.9%), and diphtheria in tetanus-diphtheria (Td) recipients (48.6%) were less favorable. Factors associated with vaccine failure include older age at immunization; lower CD3, CD4, or CD19 count; higher immunoglobulin M concentration; positive recipient cytomegalovirus serology; negative titer before immunization; history of acute or chronic GVHD; and radiation conditioning.[17]

Follow-up recommendations for transplant recipients have been published by the major North American and European transplant groups, the Centers for Disease Control and Prevention (CDC), and the Infectious Diseases Society of America.[18][19]

Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for immune system late effects information including risk factors, evaluation, and health counseling.

Late Effects of the Musculoskeletal System

Essentially all forms of cancer therapy, including surgery, chemotherapy, and radiation therapy, can affect the musculoskeletal system of a growing child or adolescent. The following outcomes affecting the musculoskeletal system are discussed: bone and joint late effects (abnormal bone and muscle growth, amputation/limb-sparing surgery, joint contracture, osteoporosis/fractures, osteonecrosis) and changes in body composition (obesity and body fatness). While these late effects are discussed individually, it is important to remember that all of the components within the musculoskeletal system are interrelated. For example, hypoplasia to a muscle group can negatively affect the function of the long bones and the resultant dysfunction can subsequently lead to disuse and osteoporosis.

Bone and Joint

Abnormal bone growth

In an age- and dose-dependent fashion, radiation can inhibit normal bone and muscle maturation and development. Radiation to the head (e.g., cranial, orbital, infratemporal, or nasopharyngeal radiation therapy) can cause craniofacial abnormalities, particularly in children treated before age 5 years or with radiation doses of 20 Gy or more.[1][2][3][4][5] Soft tissue sarcomas, such as orbital rhabdomyosarcoma and retinoblastoma are two of the more common cancer groups with these radiation fields. Often, in addition to the cosmetic impact of the craniofacial abnormalities, there can be related dental and sinus problems.

Radiation therapy can also directly affect the growth of the spine and long bones (and associated muscle groups) and can cause premature closure of the epiphyses, leading to short stature, scoliosis/kyphosis, or limb length discrepancy.[6][7][8][9][10][11][12] Orthovoltage, commonly used before 1970, delivered higher doses of radiation to the bone and was commonly related to abnormalities in bone growth. However, even with contemporary radiation therapy, if the location of the solid tumor is near an epiphysis or the spine, alterations in normal bone development can be difficult to avoid.

The effects of radiation administered to the spine on stature in survivors of Wilms tumor were assessed in the National Wilms Tumor Study (NWTS), studies 1 through 4.[7] Stature loss in 2,778 children treated on NWTS 1 to 4 was evaluated. Repeated height measurements were collected during long-term follow-up. The effects of radiation dosage, age at treatment, and chemotherapy on stature were analyzed using statistical models that accounted for the normal variation in height with gender and advancing age. Predictions from the model were validated by descriptive analysis of heights measured at ages 17 to 18 years for 205 patients. For those younger than 12 months at diagnosis who received more than 10 Gy, the estimated adult height deficit was 7.7 cm when contrasted with the nonradiation group. For those who received 10 Gy, the estimated trunk shortening was 2.8 cm or less. Among those whose height measurements in the teenage years were available, patients who received more than 15 Gy of radiation therapy were 4 to 7 cm shorter on average than their nonirradiated counterparts, with a dose-response relationship evident. Chemotherapy did not confer additional risk. The effects of radiation on the development of scoliosis have also been re-evaluated. In a group of 42 children treated for Wilms tumor from 1968 to 1994, scoliosis was seen in 18 patients, with only one patient needing orthopedic intervention.[13] Median time to development of scoliosis was 102 months (range 16–146 months). A clear dose-response relationship was seen, with children treated with lower dosages (<24 Gy) of radiation having a significantly lower incidence of scoliosis than those who received more than 24 Gy of radiation. There was also a suggestion that the incidence was lower in patients who received 10 to 12 Gy, the dosages currently used for Wilms tumor, although the sample size was small.

Also, cranial radiation therapy damages the hypothalamic-pituitary axis (HPA) in an age- and dose-response fashion, often leading to growth hormone deficiency (GHD).[14][15] If untreated during the growing years, and sometimes, even with appropriate treatment, this leads to a substantially lower final height. Patients with a central nervous system (CNS) tumor [14][16] or acute lymphoblastic leukemia (ALL)[17][18][19] treated with 18 Gy or more of cranial radiation therapy are at highest risk. Also, patients treated with total-body irradiation (TBI), particularly single fraction TBI, are at risk of GHD.[20][21][22][23] In addition, if the spine is also irradiated (e.g., craniospinal radiation therapy for medulloblastoma or early ALL therapies in the 1960s), growth can be affected by two separate mechanisms—GHD and direct damage to the spine.

Amputation and limb-sparing surgery

Amputation and limb-sparing surgery prevent local recurrence of bone tumors by removal of all gross and microscopic disease. If optimally executed, both procedures accomplish an en bloc excision of tumor with a margin of normal uninvolved tissue. The type of surgical procedure, the primary tumor site, and the age of the patient affect the risk of postsurgical complications.[24] Complications in survivors treated with amputation include stump-prosthetic problems, chronic stump pain, phantom limb pain, and bone overgrowth.[25][26] While limb-sparing surgeries may offer a more aesthetically pleasing outcome, complications have been reported more frequently in survivors undergoing these procedures compared with those treated with amputation. Complications after limb-sparing surgery include non-union, pathologic fracture, aseptic loosening, limb-length discrepancy, endoprosthetic fracture, poor joint movement, and stump-prosthesis problems.[25][27] Occasionally, refractory complications develop after limb-sparing surgery and require amputation.[28][29] A number of studies have compared functional outcomes after amputation and limb-sparing surgery, but results have been limited by inconsistent methods of functional assessment and small cohort sizes. Overall, data suggest that limb-sparing surgery results in better function than amputation, but differences are relatively modest.[25][29] Similarly, long-term quality of life outcomes among survivors undergoing amputation and limb sparing procedures have not differed substantially.[28]

Joint contractures

Hematopoietic cell transplantation with any history of chronic graft-versus-host disease is associated with joint contractures.[30][31][32]

Osteoporosis/fractures

Maximal peak bone mass is an important factor influencing the risk of osteoporosis and fracture associated with aging. Methotrexate has a cytotoxic effect on osteoblasts, resulting in a reduction of bone volume and formation of new bone.[33][34] This effect may be exacerbated by the chronic use of corticosteroids, another class of agents routinely used in the treatment of hematological malignancies and in supportive care for a variety of pediatric cancers. Radiation-related endocrinopathies, such as GHD or hypogonadism, may contribute to ongoing bone mineral loss.[35][36] In addition, suboptimal nutrition and physical inactivity may further predispose to deficits in bone mineral accretion.

Most of our knowledge about cancer and its treatment effects on bone mineralization has been derived from studies of children with ALL.[24][33] In this group, the leukemic process, and possibly vitamin D deficiency, may play a role in the alterations in bone metabolism and bone mass observed at diagnosis.[37] Antileukemic therapy causes further bone mineral density loss, [38] which has been reported to normalize over time [39][40] or to persist for many years after completion of therapy.[41][42] Clinical factors predicting higher risk for low bone mineral density include treatment with high cumulative doses of methotrexate (>40 g/m2), high cumulative doses of corticosteroids (>9 g/m2), and use of more potent glucocorticoids like dexamethasone.[41][43][44] Investigations evaluating the contribution of cranial radiation to the risk of low bone mineral density in childhood cancer survivors have yielded conflicting results.[41][45] Bone mineral density deficits that are likely multifactorial in etiology have been reported in allogeneic hematopoietic cell transplant recipients conditioned with TBI.[46][47] French investigators observed a significant risk for lower femoral bone mineral density among adult survivors of childhood leukemia treated with hematopoietic stem cell transplantation (HSCT) who had gonadal deficiency.[48] Hormonal therapy has been shown to enhance bone mineral density of adolescent girls diagnosed with hypogonadism after HSCT.[49][Level of evidence: 3iiiC]

Radiation-induced fractures can occur with doses of radiation of 50 Gy or more, as is often used in the treatment of Ewing sarcoma of the extremity.[50][51]

Osteonecrosis

Osteonecrosis (also known as aseptic or avascular necrosis) is a rare, but well-recognized skeletal complication observed predominantly in survivors of pediatric hematological malignancies treated with corticosteroids.[24][52][53][54] The condition is characterized by death of one or more segments of bone that most often affects weight-bearing joints, especially the hips and knees. Longitudinal cohort studies have identified a spectrum of clinical manifestations of osteonecrosis, ranging from asymptomatic spontaneously-resolving imaging changes to painful progressive articular collapse requiring joint replacement.[55][56] Symptomatic osteonecrosis characterized by pain, joint swelling, and reduced mobility typically presents during the first 2 years of therapy, particularly in the case of ALL. These symptoms may improve over time, persist, or progress in the years after completion of therapy. In some series, up to 40% of patients required some type of surgical procedure.[54] The prevalence of osteonecrosis has varied from 1% to 22% based on the study population, treatment protocol, method of evaluation, and time from treatment.[54][57][58][59][60][61]

The most important clinical risk factor for osteonecrosis is treatment with substantial doses of glucocorticoids, as is typical in regimens used for ALL, non-Hodgkin lymphoma, and HSCT.[59][62][63][64][65] Delayed intensification therapies for childhood ALL featuring the more potent glucocorticoid, dexamethasone, have been speculated to enhance risk since osteonecrosis was infrequently reported before this approach became more widely used in the 1990s. However, currently available results suggest that cumulative corticosteroid dose may be a better predictor of this complication.[62][66] Higher cholesterol, lower albumin, and higher dexamethasone exposure have been associated with a higher risk of symptomatic osteonecrosis, suggesting that agents like asparaginase may potentiate the osteonecrotic effect of dexamethasone.[61]

Osteonecrosis is more common in adolescents than in children, with the highest risk among those who are older than 10 years.[61][62][66][67] Osteonecrosis also occurs much more frequently in whites than in blacks.[65][66] Studies evaluating the influence of gender on the risk of osteonecrosis have yielded conflicting results, with some suggesting a higher incidence in females [55][66][67] that has not been confirmed by others.[53][55][62] Genetic factors influencing antifolate and glucocorticoid metabolism have also been linked to excess risk of osteonecrosis among survivors.[65] St. Jude Children's Research Hospital investigators observed an almost sixfold (odds ratio = 5.6; 95% confidence interval [CI], 2.7–11.3) risk of osteonecrosis among survivors with polymorphism of the ACP1 gene, which regulates lipid levels and osteoblast differentiation.[61]

Osteochondroma

Approximately 5% of children undergoing myeloablative stem cell transplantation will develop osteochondroma, a benign bone tumor that most commonly presents in the metaphyseal regions of long bones. Osteochondroma generally occurs as a single lesion, however multiple lesions may develop in the context of hereditary multiple osteochondromatosis.[68] A large Italian study reported a 6.1% cumulative risk of developing osteochondroma at 15 years posttransplant, with increased risk associated with younger age at transplant (≤3 yrs) and use of TBI.[69] Growth hormone therapy may influence the onset and pace of growth of osteochondromas.[23][70] Because malignant degeneration of these lesions is exceptionally rare, clinical rather than radiological follow-up is most appropriate, and surgery for biopsy or resection is generally unnecessary.[71]

Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for musculoskeletal system late effects information including risk factors, evaluation, and health counseling.

Late Effects of the Reproductive System

The treatment of cancer in children and adolescents may adversely affect their subsequent reproductive function. Germ cell survival may be adversely affected by radiation therapy and chemotherapy. Ovarian damage results in both sterilization and loss of hormone production because ovarian hormonal production is closely related to the presence of ova and maturation of the primary follicle. These functions are not as intimately related in the testis. As a result, men may have normal androgen production in the presence of azoospermia.

Testis

Surgery, radiation therapy, and/or chemotherapy may damage testicular function. Patients who undergo unilateral orchiectomy for testicular torsion may have subnormal sperm counts at long-term follow-up.[1][2] Retrograde ejaculation is a frequent complication of bilateral retroperitoneal lymph node dissection performed on males with testicular neoplasms,[3][4] and impotence may occur following extensive pelvic dissections to remove a rhabdomyosarcoma of the prostate.[5]

Men treated with whole-abdomen irradiation may develop gonadal dysfunction. In one study, five of ten men were azoospermic, and two were severely oligospermic when evaluated at ages 17 to 36 years following treatment with whole-abdomen irradiation for Wilms tumor at ages 1 to 11 years, with the penis and scrotum either excluded from the treatment volume, or shielded with 3 mm of lead. The testicular radiation doses varied from 796 cGy to 983 cGy.[6] Others reported azoospermia in 100% of ten men 2 to 40 months after radiation therapy doses of 140 cGy to 300 cGy to both testes.[7] Similarly, azoospermia was demonstrated in 100% of ten men following testicular radiation therapy doses of 118 cGy to 228 cGy. Recovery of spermatogenesis occurred after 44 to 77 weeks in 50% of the men, although three of the five with recovery had sperm counts below 20 x 106/ml.[8] Oligospermia or azoospermia was reported in 33% of 18 men evaluated 6 to 70 months after receiving testicular radiation doses of 28 cGy to 135 cGy.[9] In another report, none of five men who received testicular radiation doses of less than 20 cGy became azoospermic. By contrast, two who received testicular radiation doses of 55 cGy to 70 cGy developed temporary oligospermia, with recovery to sperm counts greater than 20 x 106/ml 18 to 24 months after treatment.[10] In summary, a decrease in sperm counts can be seen 3 to 6 weeks after irradiation, and depending on the dosage, recovery may take 1 to 3 years. The germinal epithelium is damaged by much lower dosages (<1 Gy) of radiation than are Leydig cells (20–30 Gy). Complete sterilization may occur with fractionated irradiation greater than doses of 2 Gy to 4 Gy.

Administration of higher radiation doses, such as 2,400 cGy, which was used for the treatment of testicular relapse of acute lymphoblastic leukemia (ALL), results in both sterilization and Leydig cell dysfunction.[11] Craniospinal irradiation produced primary germ cell damage in 17% of 23 children with ALL,[12] but in none of four children with medulloblastoma.[13] Total-body irradiation ([TBI] 950 cGy to 1575 cGy) and cyclophosphamide (60 mg/kg/day for 2 days) produced azoospermia in almost all men.[14]

Cumulative alkylating agent dose is an important factor in estimating the risk of testicular germ cell injury, but limited studies are available that correlate results of semen analyses in clinically well-characterized cohorts. A small cohort study reported normal semen quality in adult long-term survivors of childhood ALL treated with 0 to 10 g/m2 of cyclophosphamide and cranial radiation, whereas no spermatozoa were detected in semen samples from survivors treated with more than 20 g/m2 of cyclophosphamide.[15] Combination chemotherapy that includes an alkylating agent and procarbazine causes severe damage to the testicular germinal epithelium.[16][17][18][19][20] Azoospermia occurred less frequently in adults following treatment with two, rather than six, cycles of MOPP (mechlorethamine, vincristine [Oncovin], procarbazine, prednisone).[21] Elevation of the basal follicle-stimulating hormone (FSH) level, reflecting impaired spermatogenesis, was less frequent among patients receiving two courses of OPPA (vincristine, procarbazine, prednisone, doxorubicin) than among those who received two courses of OPPA in combination with two or more courses of COPP (cyclophosphamide, vincristine, procarbazine and prednisone).[22]

Most studies suggest that procarbazine contributes significantly to the testicular toxicity of combination chemotherapy regimens. The combination of doxorubicin, bleomycin, vinblastine, and dacarbazine produced oligospermia or azoospermia in adults frequently during the course of treatment. However, recovery of spermatogenesis occurred after treatment was completed, in contrast to the experience reported following treatment with MOPP.[23] Most studies suggested that prepubertal males were not at lower risk for chemotherapy-induced testicular damage than were postpubertal patients.[17][24][25][26]

Male survivors of non-Hodgkin lymphoma who underwent pelvic radiation therapy and received a cumulative cyclophosphamide dose greater than 9.5 g/m2 were at increased risk for failure to recover spermatogenesis;[27] in survivors of Ewing and soft tissue sarcoma, treatment with a cumulative cyclophosphamide dose greater than 7.5 g/m2 was correlated with persistent oligospermia or azoospermia.[28] Spermatogenesis was present in 67% of 15 men who received 200 mg/kg of cyclophosphamide prior to undergoing bone marrow transplantation (BMT) for aplastic anemia.[14] Cyclophosphamide doses exceeding 7.5 g/m2 and ifosfamide doses exceeding 60 g/m2 produced oligospermia or azoospermia in most exposed individuals.[29][30][31]

Ovary

The frequency of ovarian failure following abdominal radiation therapy is related to both the age of the woman at the time of irradiation and the radiation therapy dose received by the ovaries. Whole-abdomen irradiation produces severe ovarian damage. Seventy-one percent of women in one series failed to enter puberty and 26% had premature menopause following whole-abdominal radiation therapy doses of 2,000 cGy to 3,000 cGy.[32] Other studies reported similar results in women treated with whole-abdomen irradiation [33] or craniospinal irradiation [34][35] during childhood.

Ovarian function may be impaired following treatment with combination chemotherapy that includes an alkylating agent and procarbazine such as MOPP; MVPP (nitrogen mustard [mechlorethamine], vinblastine, procarbazine, and prednisone); ChlVPP (chlorambucil, vinblastine, procarbazine, and prednisone); MDP (doxorubicin, prednisone, procarbazine, vincristine, and cyclophosphamide); or the combination of COP (cyclophosphamide, vincristine, and procarbazine) with ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine, and dacarbazine). Amenorrhea was reported in 11% after MOPP (2 of 18 girls treated at age 2 to 15 years), 31% after MDP (10 of 31 girls treated at age 9.0 to 15.2 years), and 13% after ChIVPP (3 of 23 girls treated at age 6.1 to 20.0 years),[16][36][37] but in 0% after COP/ABVD (0 of 17 girls treated at age 4 to 20 years).[38]

Ovarian function was evaluated in women treated with drug combinations that did not include procarbazine. Ovarian function was normal in all of six women treated for non-Hodgkin lymphoma with a cyclophosphamide containing drug combination.[39] Others reported that pubertal progression was adversely affected in 5.8% of 17 patients treated before puberty compared with 33.3% of 18 patients treated during puberty or after menarche. However, the administration of cyclophosphamide did not correlate with the abnormal pubertal progression observed in these patients.[40] Administration of ifosfamide 27 g/m2 to 90 g/m2 to 13 females resulted in evidence of impaired estrogen production in only one patient.[31] Cisplatin administration resulted in amenorrhea in 14% of seven patients.[41]

All women who received high-dose (50 mg/kg/day x 4 days) cyclophosphamide prior to BMT for aplastic anemia developed amenorrhea following transplantation. In one series, 36 of 43 women had recovery of normal ovarian function 3 to 42 months after transplantation, including all of the 27 patients who were between ages 13 and 25 years at the time of BMT.[42] Most postpubertal women who receive TBI prior to BMT develop amenorrhea. In one series, recovery of normal ovarian function occurred in only 9 of 144 patients and was highly correlated with age at irradiation in patients younger than 25 years.[42] In a series restricted to patients who were prepubertal at the time of BMT, 44% (7 of 16) had clinical and biochemical evidence of ovarian failure.[43]

Of 3,390 eligible participants in the Childhood Cancer Survivor Study (CCSS), 215 (6.3%) developed acute ovarian failure. Survivors with acute ovarian failure were older (aged 13–20 years vs. aged 0–12 years) at cancer diagnosis and more likely to have been diagnosed with Hodgkin lymphoma or to have received abdominal or pelvic radiation therapy than survivors without acute ovarian failure.[44] Of survivors who developed acute ovarian failure, 75% had received abdominal-pelvic irradiation. Radiation doses to the ovary of at least 2,000 cGy were associated with the highest rate of acute ovarian failure with over 70% of such patients developing acute ovarian failure.[44] In a multivariable logistic regression model, increasing doses of ovarian irradiation, exposure to procarbazine at any age, and exposure to cyclophosphamide at ages 13 to 20 years were independent risk factors for acute ovarian failure.

The presence of apparently normal ovarian function at the completion of chemotherapy should not be interpreted as evidence that no ovarian injury has occurred. Premature menopause is well documented in childhood cancer survivors, especially in women treated with both an alkylating agent and abdominal irradiation.[45][46][47] A total of 126 childhood cancer survivors and 33 control siblings who participated in the CCSS developed premature menopause. Of these women, 61 survivors (48%) and 31 siblings (94%) had surgically-induced menopause (relative risk [RR] = 0.8; 95% confidence interval [CI] = 0.52–1.23). However, the cumulative incidence of nonsurgical premature menopause was substantially higher for survivors than for siblings (8% vs. 0.8%; RR = 13.21; 95% CI, 3.26–53.51; P < .001).[45]

A multiple Poisson regression model showed that risk factors for nonsurgical premature menopause included attained age, exposure to increasing doses of radiation to the ovaries, increasing alkylating agent dose score, and a diagnosis of Hodgkin lymphoma. For survivors who were treated with alkylating agents plus abdominal-pelvic radiation, the cumulative incidence of nonsurgical premature menopause approached 30%.[45]

In Europe, survivors of Hodgkin lymphoma treated between the ages 15 years and 40 years and who were not receiving hormonal contraceptives were surveyed for the occurrence of premature ovarian failure. In 460 women, premature ovarian failure was mainly influenced by alkylating chemotherapy use with a linear dose relationship between alkylating chemotherapy and premature ovarian failure occurrence. Premature ovarian failure risk increased by 23% per year of age at treatment. In women treated without alkylating chemotherapy before age 32 years and at age 32 years or older, cumulative premature ovarian failure risks were 3% and 9%, respectively. If menstruation returned after treatment, cumulative premature ovarian failure risk was independent of age at treatment. Among women who ultimately developed premature ovarian failure, 22% had one or more children after treatment, compared with 41% of women without premature ovarian failure. This report indicates that women with proven fertility after treatment can still face infertility problems at a later stage.[47]

Fertility was evaluated among the 5,149 female CCSS participants and 1,441 female siblings of CCSS participants, aged 15 to 44 years. The RR for ever being pregnant was 0.81 (95% CI, 0.73–0.90; P < .001) compared with female siblings. In multivariate models among survivors only, those who received a hypothalamic/pituitary radiation dose of greater than 3,000 cGy (RR = 0.61; 95% CI, 0.44–0.83) or an ovarian/uterine radiation dose greater than 500 cGy were less likely to have ever been pregnant (RR = 0.56 for 500–1000 cGy; 95% CI, 0.37–0.85; RR = 0.18 for >1000 cGy; 95% CI, 0.13–0.26). A summed alkylating agent dose score of 3 (RR = 0.72; 95% CI, 0.58–0.90; P = .003) or 4 (RR = 0.65; 95% CI, 0.45–0.96; P = .03) was associated with lower observed risk of pregnancy compared with those with no alkylating agent exposure. Those with a summed alkylating agent dose score of 3 or 4 or who were treated with lomustine or cyclophosphamide were less likely to have ever been pregnant.[49] A follow-up study of the same cohort demonstrated impaired fertility in female survivors who received modest doses (22–27 Gy) of hypothalamic pituitary radiation and no or very low doses (<0.1 Gy) of ovarian radiation, providing support for the contribution of the role of luteal phase deficiency to infertility in some women.[50]

Fertility may be impaired by factors other than the absence of sperm and ova. Conception requires delivery of sperm to the uterine cervix, patency of the fallopian tubes for fertilization to occur, and appropriate conditions in the uterus for implantation. Retrograde ejaculation occurs with a significant frequency in men who undergo bilateral retroperitoneal lymph node dissection. Uterine structure may be affected by abdominal irradiation. A study demonstrated that uterine length was significantly shorter in ten women with ovarian failure who had been treated with whole abdomen irradiation. Endometrial thickness did not increase in response to hormone replacement therapy in three women who underwent weekly ultrasound examination. No flow was detectable with Doppler ultrasound through either uterine artery of five women, and through one uterine artery in three additional women.[51]

Reproduction

For survivors who maintain fertility, numerous investigations have evaluated the prevalence of and risk factors for pregnancy complications in adults treated for cancer during childhood. Pregnancy complications including hypertension, fetal malposition, fetal loss/spontaneous abortion, preterm labor, and low birth weight have been observed in association with specific diagnostic and treatment groups.[48][49][52][53][54][55][56][57][58][59][60]

In a study of 4,029 pregnancies among 1,915 women followed in the CCSS, there were 63% live births, 1% stillbirths, 15% miscarriages, 17% abortions, and 3% unknown or in gestation. Risk of miscarriage was 3.6-fold higher in women treated with craniospinal radiation and 1.7-fold higher in those treated with pelvic radiation. Chemotherapy exposure alone did not increase risk of miscarriage. Compared with siblings, survivors were less likely to have live births, more likely to have medical abortions, and more likely to have low birth weight babies.[49] In the same cohort, another study evaluated pregnancy outcomes of partners of male survivors. Among 4,106 sexually active males, 1,227 reported they sired 2,323 pregnancies, which resulted in 69% live births, 13% miscarriages, 13% abortions, and 5% unknown or in gestation at the time of analysis. Compared with partners of male siblings, there was a decreased incidence of live births (RR = 0.77), but no significant differences of pregnancy outcome by treatment.[48]

In the National Wilms Tumor Study, records were obtained for 1,021 pregnancies of more than 20 weeks duration. In this group, there were 955 single live births. Hypertension complicating pregnancy, early or threatened labor, malposition of the fetus, lower birth weight (<2,500 g), and premature delivery (<36 weeks) were more frequent among women who had received flank radiation, in a dose-dependent manner.[56]

In a retrospective cohort analysis from the CCSS of 1,148 men and 1,657 women who had survived cancer, there were 4,946 pregnancies. Irradiation of the testes in men and pituitary gland in women and chemotherapy with alkylating drugs were not associated with an increased risk of stillbirth or neonatal death. Uterine and ovarian irradiation significantly increased the risk of stillbirth and neonatal death at doses higher than 10 Gy. For girls treated before menarche, irradiation of the uterus and ovaries at doses as low as 1 Gy to 2.49 Gy significantly increased the risk of stillbirth or neonatal death.[61]

Results from a Danish study confirm the association of uterine radiation with spontaneous but not other types of abortion. Thirty-four thousand pregnancies were evaluated in a population of 1,688 female survivors of childhood cancer in the Danish Cancer Registry. The pregnancy outcomes of survivors, 2,737 sisters, and 16,700 comparison women in the population were identified. No significant differences were seen between survivors and comparison women in the proportions of live births, stillbirths, or all types of abortions combined. Survivors with a history of neuroendocrine or abdominal radiation therapy had an increased risk of spontaneous abortion. Thus, the pregnancy outcomes of survivors were similar to those of comparison women with the exception of spontaneous abortion.[53]

Progress in reproductive endocrinology has resulted in the availability of several options for preserving or permitting fertility in patients about to receive potentially toxic chemotherapy or radiation therapy.[62] For males, cryopreservation of spermatozoa before treatment is an effective method to circumvent the sterilizing effect of therapy. Although pretreatment semen quality in patients with cancer has been shown to be less than that noted in healthy donors, the percentage decline in semen quality and the effect of cryodamage to spermatozoa from patients with cancer is similar to that of normal donors.[63][64][65][66] For those unable to bank sperm, newer technologies such as testicular sperm extraction may be an option. Further micromanipulative technologic advances such as intracytoplasmic sperm injection and similar techniques may be able to render sperm extracted surgically, or even poor-quality cryopreserved spermatozoa from cancer patients, capable of successful fertilization.[67]

Preservation of fertility and successful pregnancies may occur after hematopoietic stem cell transplantation (HSCT), though the conditioning regimens that include TBI, cyclophosphamide, and busulfan are highly gonadotoxic. In a group of 21 females who had received a BMT in the prepubertal years, 12 (57%) were found to have ovarian failure when examined between ages 11 and 21 years, and the association with busulfan was significant.[68] One study evaluated pregnancy outcomes in a group of females treated with BMT. Among 708 women who were postpubertal at the time of transplant, 116 regained normal ovarian function and 32 became pregnant. Among 82 women who were prepubertal at the time of transplant, 23 had normal ovarian function and nine became pregnant. Of the 72 pregnancies in these 41 women, 16 occurred in those treated with TBI and 50% resulted in early termination. Among the 56 pregnancies in women treated with cyclophosphamide without either TBI or busulfan, 21% resulted in early termination. There were no pregnancies among the 73 women treated with busulfan and cyclophosphamide, and only one retained ovarian function.[69]

Pregnancy outcomes

For childhood cancer survivors who have offspring, there is concern about congenital anomalies, genetic disease, or risk of cancer in the offspring. Children of cancer survivors are not at significantly increased risk for congenital anomalies stemming from their parents' exposure to mutagenic cancer treatments. A retrospective cohort analysis of validated cases of congenital anomalies among 4,699 children of 1,128 male and 1,627 female participants of the CCSS showed no significant associations between gonadal radiation or cumulative exposure to alkylating agents and congenital anomalies in offspring.[70] In a report of 2,198 offspring of adult survivors treated for childhood cancer between 1945 and 1975 compared with 4,544 offspring of sibling controls, there were no differences in the proportion of offspring with cytogenetic syndromes, single-gene defects, or simple malformations. There was similarly no effect of type of childhood cancer treatment on the occurrence of genetic disease in the offspring. A population-based study of 2,630 live-born offspring of childhood cancer survivors versus 5,504 live-born offspring of the survivors' siblings found no differences in proportion of abnormal karyotypes or incidence of Down syndrome or Turner syndrome between survivor and sibling offspring.[71] Survivors treated with abdominal radiation therapy and/or alkylating agents did not have an increased risk of offspring with genetic disease, compared with survivors not exposed to these agents.[72][73]

In a study of 5,847 offspring of survivors of childhood cancers treated in five Scandinavian countries, in the absence of a hereditary cancer syndrome (such as hereditary retinoblastoma), there was no increased risk of cancer.[74] Data from the five-center study also indicated no excess risk of single gene disorders, congenital malformations, or chromosomal syndromes among the offspring of former patients compared with the offspring of siblings.[72] (Refer to the PDQ summary on Sexuality and Reproductive Issues for more information about sexuality and reproductive issues and cancer patients.)

Most pregnancies reported by HSCT survivors and their partners result in live births. In female HSCT survivors who were exposed to TBI, there appears to be an increased risk of preterm delivery of low-birth-weight infants. Female HSCT survivors are at higher risk of needing Cesarean sections than are the normal population (42% vs. 16%). Offspring of male and female HSCT recipients do not appear to be at increased risk for birth defects, developmental delay, or cancer.[75]

Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for reproductive late effects information including risk factors, evaluation, and health counseling.

Late Effects of the Respiratory System

Acute and chronic pulmonary complications reported after treatment for pediatric malignancies include radiation pneumonitis, pulmonary fibrosis, and spontaneous pneumothorax. These sequelae are uncommon following contemporary therapy and most often result in subclinical injury that is detected only by imaging or formal pulmonary function testing. Chemotherapy agents with potential pulmonary toxicity commonly used in the treatment of pediatric malignancies include bleomycin, busulfan, and the nitrosoureas (carmustine and lomustine). These agents induce lung damage on their own or potentiate the damaging effects of radiation to the lung. Thus, the potential for acute or chronic pulmonary sequelae must be considered in the context of the specific chemotherapeutic agents and the radiation dose administered, the volume of lung irradiated, and the fractional radiation therapy doses.[1]

Acute pneumonitis manifested by fever, congestion, cough, and dyspnea can follow radiation therapy alone at doses greater than 40 Gy to focal lung volumes, or after lower doses when combined with dactinomycin or anthracyclines. Fatal pneumonitis is possible after radiation therapy alone at doses to the whole lung greater than 20 Gy, but is possible after lower doses when combined with chemotherapy. Infection, graft-versus-host disease (GVHD) in the setting of bone marrow transplant, and pre-existing pulmonary compromise (e.g., asthma) all may influence this risk. Changes in lung function have been reported in children treated with whole-lung radiation therapy for metastatic Wilms tumor. A dose of 12 Gy to 14 Gy reduced total lung capacity and vital capacity to about 70% of predicted values, and even lower if the patient had undergone thoracotomy. In a study of 48 survivors of pediatric malignant solid tumors with a median follow-up of 9.7 years following median whole-lung irradiation doses of 12 Gy (range, 10.5–18 Gy), only nine patients (18.8%) reported respiratory symptoms. However, abnormalities in forced vital capacity, forced expiratory volume in 1 second, total lung capacity, and diffusion capacity were common (58%–73%). Focal boost irradiation was also significantly associated with additional abnormalities.[2] Reducing the size of the daily radiation fractions (e.g., from 1.8 Gy per day to 1.5 Gy per day) decreases this risk.[3][4] Administration of bleomycin alone can produce pulmonary toxicity and, when combined with radiation therapy, can heighten radiation reactions. Chemotherapeutic agents such as doxorubicin, dactinomycin, and busulfan are radiomimetic agents and can reactivate latent radiation damage.[3][4][5]

The development of bleomycin-associated pulmonary fibrosis with permanent restrictive disease is dose dependent, usually occurring at doses greater than 200 U/m2 to 400 U/m2, higher than those used in treatment protocols for pediatric malignancies.[5][6][7] More current pediatric regimens for Hodgkin lymphoma using radiation therapy and ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) have shown a significant incidence of asymptomatic pulmonary dysfunction after treatment, which appears to improve with time.[8][9][10] However, grade 3 and 4 pulmonary toxicity has been reported in 9% of children receiving 12 cycles of ABVD followed by 21 Gy of radiation.[7] In addition, ABVD-related pulmonary toxicity may result from fibrosis induced by bleomycin or “radiation recall” pneumonitis related to administration of doxorubicin. Pulmonary veno-occlusive disease has been observed rarely and has been attributed to bleomycin chemotherapy.[11]

Patients undergoing hematopoietic stem cell transplant (HSCT) are at increased risk of pulmonary toxicity, related to (1) preexisting pulmonary dysfunction (e.g., asthma, pretransplant therapy); (2) the preparative regimen that may include cyclophosphamide, busulfan,
and carmustine; (3) total-body irradiation; and (4) the presence of GVHD.[12][13][14][15][16][17] Although most survivors of transplant are not clinically compromised, restrictive lung disease may occur and has been reported to increase in prevalence with increasing time from HSCT, based on limited data from longitudinally followed cohorts.[18][19] Obstructive disease is less common, as is late onset pulmonary syndrome, which includes the spectrum of restrictive and obstructive disease. Bronchiolitis obliterans with or without organizing pneumonia, diffuse alveolar damage, and interstitial pneumonia may occur as a component of this syndrome, generally between 6 and 12 months posttransplant. Cough, dyspnea, or wheezing may occur with either normal chest x-ray or diffuse/patchy infiltrates; however, most patients are symptom free.[14][20][21][22]

Additional factors contributing to chronic pulmonary toxicity include superimposed infection, underlying pneumonopathy (e.g., asthma), cigarette use, respiratory toxicity, chronic GVHD, and the effects of chronic pulmonary involvement by tumor or reaction to tumor. Lung lobectomy during childhood appears to have no significant impact on long-term pulmonary function,[23] but the long-term effect of lung surgery for children with cancer is not well defined.

The true prevalence or incidence of pulmonary dysfunction in childhood cancer survivors is not clear. For children treated with HSCT, there is significant clinical disease. No large cohort studies have been performed with clinical evaluations coupled with functional and quality of life assessments. An analysis of self-reported pulmonary complications of 12,390 survivors of common childhood malignancies has been reported by the Childhood Cancer Survivor Study.[24] This cohort includes children treated with both conventional and myeloablative therapies. Compared with siblings, survivors had an increased relative risk (RR) of lung fibrosis, recurrent pneumonia, chronic cough, pleurisy, use of supplemental oxygen therapy, abnormal chest wall, exercise-induced shortness of breath, and bronchitis, with RRs ranging from 1.2 to 13.0 (highest for lung fibrosis and lowest for bronchitis). The 25-year cumulative incidence of lung fibrosis was 5% for those who received chest radiation therapy and less than 1% for those who received pulmonary toxic chemotherapy. With changes in the doses of radiation therapy employed since the late 1980s, the incidence of these abnormalities is likely to decrease.

Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for respiratory late effects information including risk factors, evaluation, and health counseling.

Late Effects of the Special Senses

Hearing

Children treated for malignancies may be at risk for early- or delayed-onset hearing loss that can affect learning, communication, school performance, social interaction, and overall quality of life. Hearing loss as a late effect of therapy can occur after exposure to platinum compounds (cisplatin and carboplatin) and cranial irradiation. Children are more susceptible to ototoxicity from platinum agents than adults.[1][2] Risk factors associated with hearing loss with platinum agents include the following:

Younger age.

Higher cumulative dose of chemotherapy.

Central nervous system (CNS) tumors.

Concomitant CNS radiation.

For cisplatin, the risk of significant hearing loss involving the speech frequencies (500–2000 Hz) usually occurs with cumulative doses that exceed 400 mg/m2 in pediatric patients.[1][3] Ototoxicity after platinum chemotherapy can present or worsen years after completion of therapy. In 59 patients who had received cisplatin, 51% of them developed late-onset hearing loss (occurring at least 6 months after the last dose of cisplatin). Radiation to the posterior fossa and the use of hearing aids were associated with late-onset hearing loss.[4][5] Carboplatin used in conventional (nonmyeloablative) dosing is typically not ototoxic.[6] A single study observed ototoxicity after the use of non-stem cell transplant dosing of carboplatin for retinoblastoma, in that 8 children out of 175 developed hearing loss. For seven of the eight children, the onset of the ototoxicity was delayed a median of 3.7 years.[7] Another study evaluating audiological outcomes among 60 retinoblastoma survivors treated with nonmyeloablative systemic carboplatin and vincristine estimated a cumulative incidence of hearing loss of 20.3% at 10 years. Among the ten (17%) patients who developed sustained grade 3 or 4 hearing loss, nine were younger than 6 months at the start of chemotherapy. Younger age at the start of treatment was the only significant predictor of hearing loss; the cumulative incidence of hearing loss was 39% for patients younger than 6 months versus only 8.3% for patients aged 6 months and older (P = .004).[8] With myeloablative dosing, carboplatin may cause significant ototoxicity. For carboplatin, ototoxicity has been reported to occur at cumulative doses exceeding 400 mg/m2.[9]

Cranial radiation therapy, when used as a single modality, results in ototoxicity when cochlear dosage exceeds 32 Gy. Young patient age and presence of a brain tumor and/or hydrocephalus can increase susceptibility to hearing loss. The onset of radiation-associated hearing loss may be gradual, manifesting months to years after exposure. When used concomitantly with cisplatin, radiation therapy can substantially exacerbate the hearing loss associated with platinum chemotherapy.[10][11][12][13] In a report from the Childhood Cancer Survivor Study (CCSS), 5-year survivors were at increased risk of problems with hearing sounds (relative risk [RR] = 2.3), tinnitus (RR = 1.7), hearing loss requiring an aid (RR = 4.4), and hearing loss in one or both ears not corrected by a hearing aid (RR = 5.2) when compared with siblings. Temporal lobe (>30 Gy) and posterior fossa radiation (>50 Gy but also 30–49.9 Gy) was associated with these outcomes. Exposure to platinum was associated with an increased risk of problems with hearing sounds (RR = 2.1), tinnitus (RR = 2.8), and hearing loss requiring an aid (RR = 4.1).[14]

Orbital and Optic

Orbital complications are common following radiation therapy for retinoblastoma, childhood head and neck sarcomas, and CNS tumors, and as part of total-body irradiation (TBI).

For survivors of retinoblastoma, a small orbital volume may result from either enucleation or radiation therapy. Age younger than 1 year may increase risk, but this is not consistent across studies.[15][16] Progress has been made in the management of retinoblastoma with better enucleation implants, intravenous chemoreduction, and intra-arterial chemotherapy in addition to thermotherapy, cryotherapy, and plaque radiation. Longer follow-up is needed to assess the impact on vision in patients undergoing these treatment modalities.[15][17][18][19] Previously, tumors located near the macula and fovea were associated with an increased risk of complications leading to visual loss, although treatment of these tumors with foveal laser ablation has shown promise in preserving vision.[19][20][21][22][23][24][25] (Refer to the PDQ summary on Retinoblastoma Treatment for more information on the treatment of retinoblastoma.)

Survivors of orbital rhabdomyosarcoma are at risk of dry eye, cataract, orbital hypoplasia, ptosis, retinopathy, keratoconjunctivitis, optic neuropathy, lid epithelioma, and impairment of vision following radiation therapy doses of 30 Gy to 65 Gy. The higher dose ranges (>50 Gy) are associated with lid epitheliomas, keratoconjunctivitis, lacrimal duct atrophy, and severe dry eye. Retinitis and optic neuropathy may also result from doses of 50 Gy to 65 Gy and even at lower total doses if the individual fraction size is greater than 2 Gy.[26] Cataracts are reported following lower doses of 10 Gy to 18 Gy.[27][28][29][30][31][32] (Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information on the treatment of rhabdomyosarcoma in children.)

Survivors of childhood cancer are at increased risk for ocular late effects related to both glucocorticoid and radiation exposure to the eye. The Childhood Cancer Survivor Study (CCSS) reported that survivors 5 or more years from diagnosis are at increased risk for cataracts, glaucoma, legal blindness, double vision, and dry eye when compared with siblings. The dose of radiation to the eye is significantly associated with risk of cataracts, legal blindness, double vision, and dry eye, in a dose-dependent manner. Risk of cataracts was associated with a radiation dose of 3,000 cGy or more to the posterior fossa, temporal lobe and exposure to prednisone. The cumulative incidence of cataracts, double vision, dry eye, and legal blindness continued to increase up to 20 years after diagnosis for those who received more than 500 cGy to the eye.[33]

Ocular complications such as cataracts and dry-eye syndrome are common after stem cell transplant in childhood. Compared with patients treated with busulfan or other chemotherapy, patients treated with single-dose or fractionated TBI are at increased risk of cataracts. Risk ranges from approximately 10% to 60% at 10 years posttreatment, depending on the total dose and fractionation, with a shorter latency period and more severe cataracts noted after single fraction and higher dose or dose-rate TBI.[34][35][36][37] Patients receiving TBI with
biologically effective doses of less than 40 Gy have a less than 10% chance of developing severe cataracts.[37] Corticosteroids and graft-versus-host disease (GVHD) may further increase risk.[34][38] Epithelial superficial keratopathy has been shown to be more common if the patient was exposed to repeated high trough levels of cyclosporine A.[39]

Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for information on the late effects of special senses including risk factors, evaluation, and health counseling.

Late Effects of the Urinary System

Cancer treatments predisposing to late renal injury and hypertension include specific chemotherapeutic drugs (cisplatin, carboplatin, and ifosfamide), renal radiation therapy, and nephrectomy.[1] Cisplatin can cause glomerular and tubular damage resulting in a diminished glomerular filtration rate (GFR) and electrolyte wasting (particularly magnesium, calcium, and potassium). Approximately 50% of patients may experience long-lasting hypomagnesemia. The use of ifosfamide concurrently with cisplatin increases the risk of renal injury.[2] Carboplatin is a cisplatin analog and is less nephrotoxic than cisplatin. Although in a prospective longitudinal single-center cohort study of children followed for more than 10 years after completion of therapy with cisplatin or carboplatin, older age at treatment was found to be the major risk factor for nephrotoxicity, especially for patients receiving carboplatin, while cisplatin dose schedule and cumulative carboplatin dose were also important predictors of toxicity. Platinum nephrotoxicity did not change significantly over 10 years.[3] The combination of carboplatin/ifosfamide may be associated with more renal damage than the combination of cisplatin/ifosfamide.[3][4][5] As with ototoxicity, however, additional follow-up in larger numbers of survivors treated with carboplatin must be evaluated before potential renal toxicity can be better defined.

Ifosfamide can also cause glomerular and tubular toxicity, with renal tubular acidosis, and Fanconi syndrome, a proximal tubular defect characterized by impairment of resorption of glucose, amino acids, phosphate, and bicarbonate. Ifosfamide doses greater than 60 g/m2 to 100 g/m2, age younger than 5 years at time of treatment, and combination with cisplatin and carboplatin increase the risk of ifosfamide-associated renal tubular toxicity.[6][7][8] Abnormalities in glomerular filtration are less common, and when found, are usually not clinically significant. More common are abnormalities with proximal tubular function greater than distal tubular function, though the prevalence of these findings is uncertain and further study of larger cohorts with longer follow-up is required.[2][9][10][11][12] A French study evaluating the incidence of late renal toxicity after ifosfamide reported normal tubular function in 90% of pediatric cancer survivors (median follow-up of 10 years); 79% of the cancer survivors had normal GFR, and all had normal serum bicarbonate and calcium. Hypomagnesemia and hypophosphatemia were seen in 1% of cancer survivors. Glycosuria was detected in 37% of cancer survivors but was mild in 95% of cases. Proteinuria was observed in 12% of cancer survivors. In multivariate analysis, ifosfamide dose and interval from therapy were predictors of tubulopathy, and older age at diagnosis and interval from therapy were predictors of abnormal GFR.[8]

High-dose methotrexate (1,000–33,000 mg/m2) has been reported to cause acute renal dysfunction in 0% to 12.4% of patients. This has resulted in delayed elimination of the drug, but long-term renal sequelae have not been described.[13]

Irradiation to the kidney can result in radiation nephritis or nephropathy after a latent period of 3 to 12 months. Doses greater than 20 Gy can result in significant nephropathy.[14] In a report from the German Registry for the Evaluation of Side Effects after Radiation in Childhood and Adolescence (RISK consortium), 126 patients who underwent radiation therapy to parts of the kidneys for various cancers were evaluated. All patients also received potentially nephrotoxic chemotherapy. Whole kidney volumes exposed to greater than 20 Gy (P = .031) or 30 Gy (P = .003) of radiation were associated with a greater risk for mild degrees of nephrotoxicity.[15] The effect of radiation therapy on the kidney has best been examined in survivors of pediatric Wilms tumor. Generally, studies have shown that the risk of renal insufficiency is higher among children receiving higher doses of radiation.[16][17][18] A correlation between functional impairment and the renal radiation dose was reported in a study of 100 children treated for Wilms tumor. The incidence of impaired creatinine clearance was significantly higher for children receiving more than 12 Gy to the remaining kidney, and all cases of overt renal failure occurred after more than 23 Gy.[19] In a cohort of Wilms tumor survivors evaluated 5 years after receiving abdominal radiation, the prevalence of renal insufficiency, as defined by hypertension, was approximately 7%.[20]

Data from the National Wilms Tumor Study Group and the U.S. Renal Data System indicate that the 20-year cumulative incidence of end-stage renal disease (ESRD) in children with unilateral Wilms tumor and Denys-Drash syndrome is 74%, 36% for those with WAGR (Wilms tumor, aniridia, genitourinary abnormalities, mental retardation) syndrome, 7% for male patients with genitourinary anomalies and 0.6% for 5,347 patients with none of these conditions.[21] For patients with bilateral Wilms tumors, the incidence of ESRD is 50% for Denys-Drash syndrome, 90% for WAGR, 25% for genitourinary anomaly, and 12% for patients for all others.[21][22] ESRD in patients with WAGR and genitourinary anomalies tended to occur relatively late, and often during or after adolescence.[21]

Treatment for Wilms tumor without flank or abdominal radiation therapy was not associated with significant nephrotoxicity in a study of 40 Wilms tumor survivors treated in England.[18]

In the setting of hematopoietic cell transplantation, fewer than 15% of children will develop chronic renal insufficiency or hypertension; the risk is related to the nephrotoxic agents used and the cumulative total-body irradiation dose, fractionation scheme, and interfraction interval. More specifically, the radiation-associated risk rises when the total dose exceeds 12 Gy, the individual fraction size is greater than 2 Gy, or the interval-fraction is less than 4 to 6 hours.[23][24][25][26]

Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for urinary late effects information including risk factors, evaluation, and health counseling.

Added text about the results of the St. Jude Total XV study regarding the risk of cognitive deficits following CNS-directed therapy with chemotherapy alone and the need for longitudinal follow-up (cited Conklin et al. as reference 20).

Late Effects of the Digestive System

Added Lee et al. as reference 56.

Late Effects of the Endocrine System

Added Thyroid nodules
as a new subsection.

Revised Table 7 to include mIBG as a predisposing therapy for thyroid nodules.

Added Paris et al. as reference 65.

Late Effects of the Musculoskeletal System

Revised text to state that symptomatic osteonecrosis characterized by pain, joint swelling, and reduced mobility typically presents during the first 2 years of therapy, particularly in the case of acute lymphoblastic leukemia. Also added text to state that in some series, up to 40% of patients required some type of surgical procedure (cited Mattano et al. as reference 54).

Late Effects of the Special Senses

Added text about a study that evaluated audiological outcomes among 60 retinoblastoma survivors treated with nonmyeloablative systemic carboplatin and vincristine and reported on the cumulative incidence of hearing loss in those patients; younger age at the start of treatment was the only significant predictor of hearing loss (cited Qaddoumi et al. as reference 8).

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is
editorially independent of NCI. The summary reflects an independent review of
the literature and does not represent a policy statement of NCI or NIH. More
information about summary policies and the role of the PDQ Editorial Boards in
maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the late effects of treatment for childhood cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

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